PT1853251E - Halogen-substituted boronophthalides for the treatment of infections - Google Patents

Description

DESCRIPTION

BOROFTALIDAS REPLACED WITH HALOGEN FOR TREATMENT

OF INFECTIONS

BACKGROUND OF THE INVENTION

Nail and hull infections, known as nail and periungual, pose serious problems in dermatology. These nail and / or periungual infections can be caused by sources such as fungi, viruses, yeasts, bacteria and parasites. Onychomycosis is an example of such severe nail and / or periungual infections and is caused by at least one fungus. Current treatment for these nail and / or periungual infections generally falls into three categories: systemic drug administration; surgical removal of all or part of the nail or the hull, followed by topical treatment of the exposed tissue or topical application of conventional creams, lotions, gels or solutions, often including the use of bandages to hold such pharmaceutical forms in place on the nail or the nail. hull. All these approaches have significant drawbacks. The following discussion is particularly directed to the disadvantages associated with the current antifungal treatment of nail and / or periungual infections.

To produce a therapeutic effect on the nail bed, long-term systemic (oral) administration of an antifungal agent for the treatment of onychomycosis is often required. For example, oral treatment with the antifungal compound ketoconazole normally requires administration of 200 to 400 mg / day for 6 months, before any significant therapeutic benefit arises. This long-term treatment with systemic high dose therapy has considerable adverse effects. For example, it has been reported that ketoconazole has toxic effects on the liver and reduces blood testosterone levels due to adverse effects on the testis. There is a problem of cooperation on the part of the patient in such long therapies, especially in those involving serious adverse effects. In addition, this type of long-term oral therapy is inconvenient in treating a horse or other ruminant affected with fungal infections in the hooves. Therefore, the risks associated with parenteral treatments considerably discourage their use and generate a significant lack of cooperation on the part of the patient. Surgical removal of all or part of the nail followed by topical treatment also has serious drawbacks. The pain and discomfort associated with surgery and the undesirable aesthetic appearance of the nail or nail bed are serious problems, particularly for female patients and those most sensitive to physical appearance. Generally, this type of treatment is not realistic for ruminants like horses. Topical therapy also has significant problems. Topical dosage forms such as creams, lotions, gels, etc., can not keep the drug in close contact with the infected area for therapeutically effective periods of time. Bandages were used to hold drug reservoirs in place in an attempt to increase the uptake of the pharmaceutical agent. However, bandages are thick, uncomfortable, uncomfortable and often lead to a lack of cooperation on the part of patients.

Hydrophilic and hydrophobic films have also been developed constituting topical antifungal solutions. 2

These dosage forms improve contact between the drug and the nail, but the films are not occlusive. Topical formulations for the treatment of fungal infection have primarily attempted to deliver the drug to the target site (an infected nail bed) by diffusion on or through the nail. The nail resembles hair more than the stratum corneum in terms of physical composition and permeability. Nitrogen is the main component of the nail as it buys the proteinic nature of the nail. The total lipid content of a developed nail is 0.1-1.0%, while the lipid of the stratum corneum is about 10% m / m. The nail is 100-200 times thicker than the stratum corneum and has an affinity and ability to bind and retain very high antifungal drugs. Accordingly, little or no drug penetrates through the nail to reach the target site. For these reasons, topical therapy of fungal infections has generally been ineffective.

Compounds known as penetration or permeation enhancers are well known in the art to produce an increase in permeability of the skin, or other body membranes, to a pharmacologically active agent. Greater permeability allows an increase in how quickly the drug crosses the skin and enters the bloodstream. Penetration enhancers have been successful in overcoming the impermeability of pharmaceutical agents through the skin. However, the layer of stratum corneum of the skin, which has a thickness of about 10 to 15 cells and is formed naturally by cells migrating from the basal layer to the skin surface, has been easier to penetrate than the nails. Furthermore, the utility of penetration enhancers in facilitating drug migration through the nail tissue has not been found.

Antimicrobial compositions for controlling bacterial and fungal infections comprising an 8-hydroxyquinoline metal chelate and an alkylbenzenesulfonic acid have proved effective because of the greater ability of the oleophilic group to penetrate the lipid layers of microcells. However, the compounds do not effectively enhance the ability to carry the pharmaceutically active antifungal through the cornified layer or stratum corneum of the skin. Pat. U.S. Patent No. 4,602,011, West et al., Jul. 22, 1986;

Pat. US-A-5,880,188 discloses oxaborols, including benzoxaborols, and their use as biocides. The disclosed compounds include 5-fluorobenzoxaborol and 5-chlorobenzoxaborol and the patent shows that particularly useful effects have been obtained with 6-chloro-5-fluoro- or 5-bromobenzoxoborol and some of their esters in plastic materials and paint films.

Therefore, there is a need in the art for compounds which can effectively penetrate the nail. There is also a need in the art for compounds which can effectively treat nail and / or periungual infections. The present invention addresses these and other needs.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides a product for use as a medicament and is selected from a compound having the structure:

F OH /

and the pharmaceutically acceptable salts thereof, optionally wherein the salt is a base addition salt obtained by contacting the neutral form of that compound with a sufficient amount of the desired base in a suitable inert solvent.

In a second aspect, there is provided a product for use as a medicament and selected from a compound having the structure:

and pharmaceutically acceptable salts thereof, optionally wherein the salt is a base addition salt obtained by contacting the neutral form of that compound with a sufficient amount of the desired base in a suitable inert solvent.

A further aspect is a formulation for pharmaceutical use which comprises: (a) a pharmaceutically acceptable excipient; and (b) a compound having the structure:

or pharmaceutically acceptable salts thereof, optionally wherein the salt is a base addition salt obtained by contacting the neutral form of that compound with a sufficient amount of the desired base in a suitable inert solvent.

Also included in the invention is the use in the cosmetic area of a compound having the structure:

or pharmaceutically acceptable salts thereof, optionally wherein the salt is a base addition salt obtained by contacting the neutral form of that compound with a sufficient amount of the desired base in a suitable inert solvent; provided that the use is not a method of treatment of the human or animal body by surgery or therapy. The invention further provides a topical gel formulation comprising: (a) a compound of the formula:

or pharmaceutically acceptable salts thereof, optionally wherein the salt is a base addition salt obtained by contacting the neutral form of that compound with a sufficient amount of the desired base in a suitable inert solvent; and (b) a support of the gel phase.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a table with minimal inhibitory concentration (MIC) data of Cl and CIO compounds against various fungi. FIG. 2A shows the minimal inhibitory concentration (MIC) for CIO, cyclopirox, terfinafine, fluconazole and itracopazole (comparison drugs) against 19 strains of test fungi. FIG. 2B shows the minimal inhibitory concentration (MIC) for CIO, cyclopirox, terfinafine, fluconazole and itracopazole (comparison drugs) against 2 strains of test fungi. FIG. 3 presents a comparison of Normalized and Equivalent CIO of Cyclopirox to each Part of Ungual Plate Samples after 14 days of Treatment. FIG. 4 presents a comparison of Cyclopirox Normalized and Equivalent CIO in Cotton Balls Support Bed Samples after 14 days of Treatment. FIG. 5 presents the results of a placebo for CIO (propylene glycol and ethyl acetate 50:50) applied per day over five days. It was observed a full growth of a carpet of the organism T. rubrum. FIG. 6 shows the results of an aliquot of 40 μl 1 / οιη2 of 10% m / v solution of CIO applied per day over five days. Inhibition zones (in the order of cells shown in the figure) of 100%, 67%, 46%, 57%, 38% and 71% were observed for the growth of T. rubrum. The green arrow indicates the measurement of the zone of inhibition. FIG. 7 shows the results of an aliquot of 40 μl / cm 2 of 10% w / v solution of CIO applied per day over five days. Inhibition zones (in the order of the cells shown in the figure) of 74%, 86%, 100% and 84% for the growth of T. rubrum were observed. FIG. 8 shows the results of an aliquot of 40 pL / cm2 of 8% m / m cyclopirox in commercial varnish applied per day over five days. No zone of inhibition was observed; full growth of a T. rubrum organism carpet. FIG. 9 shows the results of an aliquot of 40 μl 1 / οιη 2 of 5% amorolfine in commercial varnish applied per day over five days. No zone of inhibition was observed; full growth of a T. rubrum organism carpet.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions and Abbreviations

The abbreviations used herein generally have the conventional meanings in the techniques of chemistry and biology.

&Quot; Public " and related terms as used herein refer to the compounds discussed herein, pharmaceutically acceptable prodrugs and salts of such compounds. MIC, or minimal inhibitory concentration, is the point at which the compounds hold more than 90% cell growth relative to an untreated control. The term " poly " as used herein means at least 2. For example, a polyvalent metal ion is a metal having a valence of at least 2. " Fraction " refers to the radical of a molecule which is linked to another moiety.

By " effective amount of a drug, formulation or penetrator " is meant a sufficient amount of an active agent to provide the desired local or systemic effect. A " topically effective ", " cosmetically effective " or " pharmaceutically effective " or " therapeutically effective " refers to the amount of drug required to produce the desired therapeutic effect. " Topically effective " refers to a material which, when applied to the skin, nail, hair, claw or hull produces a pharmacologically desired result either locally at the site of application or systemically as a result of transdermal passage of an active ingredient from the material. &Quot; Cosmetically effective " refers to a material which, when applied to the skin, nail, hair, qarra or hull produces a desired cosmetic result, locally, at the site of application of an active ingredient of the material. The term " pharmaceutically acceptable salts " is intended to include compounds of the invention which are prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein.

Base addition salts can be obtained by contacting the compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, amino-organic or magnesium salt or a similar salt.

The starting forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compounds in a conventional manner. The source forms of the compounds differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

Certain compounds of the present invention may exist in unsolvated forms, as well as in solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated ones and are included within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be included within the scope of the present invention.

The compounds of the present invention may further include artificial proportions of atomic isotopes in one or more of the constituent atoms thereof. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodide-125 (125I) or carbon-14 (14C). All isotopic variants of the compounds of the present invention, whether reactive or not, are intended to be included within the scope of the present invention. The term " pharmaceutically acceptable carrier " or " pharmaceutically acceptable carrier " refers to any formulation or carrier medium that provides for the adequate release of an effective amount of an active agent as defined herein which does not interfere with the efficacy of the biological activity of the active agent and which is sufficiently non-toxic to the host or patient . Representative carriers include water, oils, both vegetable and mineral, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, thickeners, penetration enhancers and the like. Its formulation is well known to those skilled in cosmetics and topical medicines. Further information can be found regarding supports in Remington: The Science and Practice of Pharmacy, 21 st Ed., Lippincott, Williams & Wilkins (2005) incorporated herein by reference. The term " pharmaceutically acceptable topical support " and equivalent terms refer to pharmaceutically acceptable carriers, as described hereinbefore, suitable for topical application. An inactive, liquid or cream vehicle capable of suspending or dissolving the active agent (s) and having the properties of being non-toxic and non-inflammatory when applied to the skin, nail, hair, claw or hull is an example of a pharmaceutically acceptable topical support. The term specifically aims to include approved media materials also for use in topical cosmetics. The term " pharmaceutically acceptable additive " refers to preservatives, anti-oxidants, fragrances, emulsifiers, pigments and excipients known or used in the field of the pharmaceutical formulation and which do not unduly interfere with the efficacy of the biological activity of the active agent and which are sufficiently non-toxic to the host or patient . Additives for topical formulations are well known in the art and may be added to the topical composition provided that they are pharmaceutically acceptable and non-deleterious to epithelial cells or their function. In addition, they should not cause deterioration in the stability of the composition. For example, inert fillers, anti-irritants, tackifiers, excipients, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactants, emollients, preservatives, buffering agents, other permeation enhancers and other conventional components of topical or topical release formulations. transdermal administration as are known in the art.

The terms " enhancer ", " penetration enhancer " or " permeation enhancer " relate to an increase in the permeability of the skin, nail, hair, claw or hull relative to a drug, in order to increase the rate at which the drug penetrates through the skin, nail, hair, claw or helmet. The increase in permeation obtained through the use of enhancers may be seen, for example, by measuring the rate of diffusion of the drug through the animal or human skin, nail, hair, claw or hoof using a diffusion cell device . A diffusion cell is described by Merritt et al. Diffusion Apparatus for Skin Penetration, J of Controlled Release, 1 (1984) pp. 161-162. The term " permeation enhancer " or " penetration enhancer " refers to an agent or a mixture of agents which, alone or in combination, act to increase the permeability of the skin, nail, hair, claw or hull relative to a drug. The term " excipients " is intended conventionally to mean carriers, diluents and / or carriers used in formulating drug compositions effective for the desired use. The term " topical administration " refers to the application of a pharmaceutical agent to the external surface of the skin, nail, hair, claw or hull so that the agent crosses the outer surface of the skin, nail, hair, claw or hull and between the underlying tissues. Topical administration includes application of the composition to intact skin, nail, hair, claw and hull or to damaged, raw or open wound skin, nail, hair, claw or hull. Topical administration of a pharmaceutical agent may result in a limited distribution of the agent on the surrounding skin and tissues or, when the active agent is removed from the treatment zone through the blood stream, may result in a systemic delivery of the agent. The term " transdermal release " refers to the diffusion of an agent through the skin barrier, nail, hair, claw or hull as a result of topical administration or other application of a composition. The stratum corneum acts as a barrier and few pharmaceutical agents capable of penetrating intact skin. In contrast, the epidermis and dermis are permeable to many solutes and thus the absorption of drugs occurs more easily through the skin, nail, hair, claw or hull that are irritated or otherwise devoid of stratum corneum with the exposed epidermis. The transdermal delivery includes injection or other form of delivery through any portion of the skin, nail, hair, claw or hull or mucous membrane and absorption or permeation through the remaining portion. Absorption through intact skin, nail, hair, claw or hull may be increased by placing the active agent in a suitable, pharmaceutically acceptable carrier prior to application to the skin, nail, hair, claw or helmet. Passive topical administration may consist of applying the active agent directly to the treatment site in combination with emollients or permeation enhancers. As used herein, the transdermal delivery is intended to include release by permeation through or through the integument, i.e. skin, nail, hair, claw or helmet. II. The present invention provides boron compounds for the uses described herein and discloses methods for the preparation of such compounds. III. The compounds The compound has a structure which is selected from:

The compounds may form a hydrate with water, solvates with alcohols such as methanol, ethanol, propanol and the like; adducts with amino compounds such as ammonia, methylamine, ethylamine and the like; adducts with acids such as formic acid, acetic acid and the like; complexes with ethanolamine, quinoline, amino acids and the like.

Preparation of small molecules containing boron

The following exemplary schemes illustrate methods of preparing boron-containing molecules of the present invention. These methods are not limited to the production of the shown compounds, but may be used to prepare a variety of molecules such as the compounds and complexes described herein. The compounds of the present invention may also be synthesized by methods not explicitly illustrated in the schemes, but well known to those skilled in the art. The compounds may be prepared using readily available materials from known intermediates.

In the following schemes, X is boron or iodine. Y is selected from H, lower alkyl and arylalkyl. Z represents H. PG is protecting group. The remaining symbols represent the atoms or fractions found in the corresponding positions of the compounds to which the invention relates. 15

Preparation Strategy # 1

In Scheme 1, Steps 1 and 2, compounds 1 or 2 are converted to alcohol 3. In step 1, compound 1 is treated with a reducing agent in an appropriate solvent. Suitable reducing agents include borane complexes such as borane-tetrahydrofuran, borane-dimethylsulfide, combinations thereof, and the like. Lithium aluminum hydride or sodium borohydride may also be used as reducing agents. The reducing agents may be used in amounts of from 0.5 to 5 equivalents, relative to compound 1 or 2. Suitable solvents include diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, combinations thereof and the like . Reaction temperatures range from 0 ° C to the boiling point of the solvent used; the times for complete reaction range from 1 to 24 h.

In Step 2, the carbonyl group of compound 2 is treated with a reducing agent in an appropriate solvent. Suitable reducing agents include borane complexes such as borane-tetrahydrofuran, borane-dimethylsulfide, combinations thereof, and the like. Lithium aluminum hydride or sodium borohydride may also be used as reducing agents. The reducing agents may be used in amounts of from 0.5 to 5 equivalents, relative to compound 2. Suitable solvents include lower alcohol, such as methanol, ethanol and propanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1 , 2-dimethoxyethane, combinations thereof and the like. Reaction temperatures range from 0 ° C to the boiling point of the solvent used; the times for complete reaction range from 1 to 24 h.

In Step 3, the hydroxyl group of compound 3 is protected with a protecting group which is stable under neutral or basic conditions. The protecting group is usually selected from methoxymethyl, ethoxyethyl, tetrahydropyran-2-yl, trimethylsilyl, tert-butyldimethylsilyl, tributylsilyl, combinations thereof and the like. In the case of methoxymethyl, compound 3 is treated with 1 to 3 equivalents of chloromethyl methyl ether in the presence of a base. Suitable bases include sodium hydride, potassium tert-butoxide, tertiary amines, such as diisopropylethylamine, triethylamine, 1,8-diazabicyclo [5.4] undec-7-ene, and inorganic bases such as sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, combinations thereof and the like. The bases may be used in amounts of from 1 to 3 equivalents, relative to compound 3. The reaction temperatures range from 0 ° C to the boiling point of the solvent used, preferably from 0 to 40 ° C; the times for complete reaction range from 1 to 48 h.

In the case of tetrahydrofuran-2-yl, compound 3 is treated with 1 to 3 equivalents of 3,4-dihydro-2 H -pyran in the presence of 1 to 10 mol% of acid catalyst. Suitable acid catalysts include pyridinium p-toluenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, hydrogen chloride, sulfuric acid, combinations thereof and the like. Suitable solvents include dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, benzene and acetonitrile, combinations thereof and the like. Reaction temperatures range from 0 ° C to the boiling point of the solvent used; the times for complete reaction range from 1 to 48 h.

In the case of trialkylsilyl, compound 3 is treated with 1 to 3 equivalents of chlorotrialkylsilane in the presence of 1 to 3 equivalents of base. Suitable bases include tertiary amines, such as imidazole, diisopropylethylamine, triethylamine, 1,8-diazabicyclo [5.4] undec-7-ene, combinations and the like. Reaction temperatures range from 0 ° C to the boiling point of the solvent used, preferably 0-40 ° C; the times for complete reaction range from 1 to 48 h.

In Step 4, compound 4 is converted to boronic acid (5) through a metal halide exchange reaction. Compound 4 is treated with 1 to 3 equivalents of alkylmetal reagent relative to compound 4, such as n-butyllithium, sec-butyllithium, tert-butyllithium or isopropylmagnesium chloride, followed by 1 to 3 equivalents of borate in relation to compound 4, such as trimethyl borate, triisopropyl borate or tributyl borate. Suitable solvents include tetrahydrofuran, ether, 1,4-dioxane, 1,2-dimethoxyethane, toluene, hexanes, combinations thereof and the like. The alkylmetal reagent may also be added in the presence of trialkyl borate. Butyllithium is added at -100 to 0 ° C, preferably -80 to -40 ° C. The isopropylmagnesium chloride is added at -80 to 40 ° C, preferably -20 to 30 ° C. After addition of the trialkyl borate, the reaction mixture is allowed to warm to room temperature, which is usually 15 to 30 ° C. When the alkylmetal reagent is added in the presence of trialkyl borate, the reaction mixture is allowed to warm to room temperature after addition. The times for complete reaction range from 1 to 12 h. Compound 5 may be non-isolated and may be used in the next step without purification or in a single reactor.

In Step 5, the protecting group of compound 5 is removed under acidic conditions to give the compound of Formulas (I) and (II). Suitable acids include acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid and the like. The acids may be used in amounts of from 0.1 to 20 equivalents, relative to compound 5. When the protecting group is trialkylsilyl, basic reagents such as tetrabutylammonium fluoride may also be used. Suitable solvents include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, propanol, acetonitrile, acetone, combinations thereof and the like. Reaction temperatures range from 0 ° C to the boiling point of the solvent used, preferably between 10 and 40 ° C; the times for complete reaction range from 0.5 to 48 h. 19

Scheme 1

Z 2

Step 5:

Palladium (II) dichloride, acetoacetonate dichloride (triphenylphosphine) palladium, bis (triphenylphosphine) palladium, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), combinations thereof and the like. The catalyst may be used in amounts of from 1 to 5 mol% relative to compound 2. Suitable ligands include triphenylphosphine, tri (o-tolyl) phosphine, tricyclohexylphosphine, combinations thereof and the like. The ligand can be used in amounts of from 1 to 5 equivalents relative to compound 2. Suitable bases include sodium carbonate, potassium carbonate, potassium phenoxide, triethylamine, combinations thereof and the like. The base may be used in amounts of from 1 to 5 equivalents relative to compound 2. Suitable solvents include N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, combinations thereof and the like. Reaction temperatures range from 20 ° C to the boiling point of the solvent used, preferably from 50 to 150 ° C; the times for complete reaction range from 1 to 72 h. The pinacol ester is then oxidatively cleaved to give compound 6. The pinacol ester is treated with sodium periodate followed by acid. Sodium periodate can be used in amounts of from 2 to 5 equivalents relative to compound 6. Suitable solvents include tetrahydrofuran, 1,4-dioxane, acetonitrile, methanol, ethanol, combinations thereof and the like. Suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, combinations thereof and the like. Reaction temperatures range from 0 ° C to the boiling point of the solvent used, preferably 0-50 ° C; the times for complete reaction range from 1 to 72 h. 21

In Step 7, the carbonyl group of compound 6 is treated with a reducing agent in an appropriate solvent to give a compound of Formulas (I) and (II). Suitable reducing agents include borane complexes such as borane-tetrahydrofuran, borane-dimethylsulfide, combinations thereof, and the like. Lithium aluminum hydride or sodium borohydride may also be used as reducing agents. The reducing agents may be used in amounts of from 0.5 to 5 equivalents, relative to compound 6. Suitable solvents include lower alcohol, such as methanol, ethanol and propanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, 2-dimethoxyethane, combinations thereof and the like. Reaction temperatures range from 0 ° C to the boiling point of the solvent used; the times for complete reaction range from 1 to 24 h.

Scheme 2

CR1

Step 7: SiD, A '8' and JF I or H, R 1 = H, W = (CR 6 R 7) m, m = 0

Preparation Strategy # 3

In Scheme 3, Step 8, the compounds of Formulas (I) and (II) may be prepared in one step from compound 3. Compound 3 is mixed with trialkyl borate, then treated with alkylmetal reagents. Suitable alkylmetal reagents include n-butyllithium, sec-butyllithium, tert-butyl lithium, combinations thereof and the like. Suitable trialkyl borates include trimethyl borate, triisopropyl borate, tributyl borate, combinations thereof and the like. Butyllithium is added at -100 to 0 ° C, preferably -80 to -40 ° C. The reaction mixture is allowed to warm to room temperature after addition. The times for complete reaction range from 1 to 12 h. Trialkyl borate may be used in amounts of from 1 to 5 equivalents relative to compound 3. The alkylmetal reagent may be used in amounts of from 1 to 2 equivalents relative to compound 3. Suitable solvents include tetrahydrofuran, ether, 4-dioxane, 1,2-dimethoxyethane, toluene, hexanes, combinations thereof and the like. The times for complete reaction range from 1 to 12 h. Alternatively, the mixture of compound 3 and trialkyl borate can be refluxed for 1 to 3 h and the alcohol molecule that forms in the ester exchange sequence can be removed by distillation prior to the addition of the alkyl metal reagent.

Scheme 3 Step 8 K-1. ## STR14 ## In Scheme 4, Step 10, the methyl group of the bromo-substituted compound is prepared as described in Scheme 4, Step 10, using N-bromosuccinimide. Bromosuccinimide can be used in amounts of 0.9 to 1.2 equivalents relative to compound 7. Suitable solvents include carbon tetrachloride, tetrahydrofuran, 1,4-dioxane, chlorobenzene, combinations thereof and the like. Reaction temperatures range from 20 ° C to the boiling point of the solvent used, preferably from 50 to 150 ° C; the times for complete reaction range from 1 to 12 h.

In Step 11, the bromomethylene group of compound 8 is converted to benzyl alcohol 3. Compound 8 is treated with sodium acetate or potassium acetate. These acetates may be used in amounts of from 1 to 10 equivalents relative to compound 8. Suitable solvents include tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, combinations and the like. Reaction temperatures range from 20 ° C to the boiling point of the solvent used, preferably from 50 to 100 ° C; the times for complete reaction range from 1 to 12 h. The resulting acetate is hydrolyzed to give compound 3 under basic conditions. Suitable bases include sodium hydroxide, lithium hydroxide, potassium hydroxide, combinations thereof and the like. The base may be used in amounts of from 1 to 5 equivalents relative to compound 8. Suitable solvents include methanol, ethanol, tetrahydrofuran, water, combinations thereof and the like. Reaction temperatures range from 20 ° C to the boiling point of the solvent used, preferably from 50 to 100 ° C; the times for complete reaction range from 1 to 12 h. Alternatively, compound 8 can be directly converted to compound 3 under similar conditions as above.

Steps 3 to 5 convert compound 3 to a compound of Formulas (I) and (II). 24

Scheme 4

.

Upon

Steps 3 to 5 I or H, R 1 = H, W = (CR 6 R 7) m, m = 0

Preparation Strategy # 5

In Scheme 5, Step 12, compound 2 is treated with (methoxymethyl) triphenylphosphonium chloride or (methoxymethyl) triphenylphosphonium bromide in the presence of base, followed by acid hydrolysis to give compound 9. Suitable bases include sodium hydride, potassium tert-butoxide, lithium diisopropylamide, butyllithium, lithium hexamethyldisilazane, combinations thereof and the like. The (methoxymethyl) triphenylphosphonium salt may be used in amounts of from 1 to 5 equivalents relative to compound 2. The base may be used in amounts of from 1 to 5 equivalents relative to compound 2. Suitable solvents include tetrahydrofuran, 1 , 2-dimethoxyethane, 1,4-dioxane, ether, toluene, hexane, N, N-dimethylformamide, combinations thereof and the like. The reaction temperatures range from 0 ° C to the boiling point of the solvent used, preferably between 0 and 30 ° C; the times for complete reaction range from 1 to 12 h. The enol ether formed under acidic conditions is hydrolyzed. Suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid and the like. Suitable solvents include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, methanol, ethanol, combinations thereof and the like. Reaction temperatures range from 20 ° C to the boiling point of the solvent used, preferably from 50 to 100 ° C; the times for complete reaction range from 1 to 12 h.

Steps 2 to 5 convert compound 9 to a compound of Formulas (I) and (II).

Scheme 5

I or H, R1 = H

Preparation Strategy # 6

In Scheme 6, the compound (I) in which R1 is H is converted to the compound (I) in which R1 is alkyl, by mixing with the corresponding alcohol, R1OH. Suitable solvents include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, combinations thereof and the like. The alcohol (R 1 OH) may also be used as the solvent. Reaction temperatures range from 20 ° C to the boiling point of the solvent used, preferably from 50 to 100 ° C; the times for complete reaction range from 1 to 12 h.

Step 13, G. H, R1 = Η I or H, R1 * ..

Preparation Strategy # 7

In Scheme 7, the compound (Ia) is converted to its amino alcohol (Ib) complex. Compound (Ia) is treated with HOR1 NR11 R11. The amino alcohol may be used in amounts of from 1 to 10 equivalents relative to the compound (Ia). Suitable solvents include methanol, ethanol, propanol, tetrahydrofuran, acetone, acetonitrile, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N, N-dimethylformamide, water, their combinations and the like. Reaction temperatures range from 20 ° C to the boiling point of the solvent used, preferably from 50 to 100 ° C; the times for complete reaction range from 1 to 12 h.

Scheme 7

Step 3

I was or was

Ib or Ilb

The compounds of Formulas (I) or (II) may be converted to hydrates and solvates by methods similar to those described above. IV. Methods to Inhibit Growth of Microorganisms or Kill Microorganisms 27

Benzoxaborols can be used with the structures disclosed herein in a method of inhibiting the growth of a microorganism or killing a microorganism, or both, comprising contacting the microorganism with a said compound. Microorganisms are selected from fungi, yeasts, viruses, bacteria and parasites. In another exemplary embodiment, the microorganism is on the inside or on the surface of an animal. In an exemplary embodiment, the animal is a member selected from human, bovine, deer, reindeer, goat, common bee, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat , camel, yak, elephant, ostrich, otter, chicken, duck, goose, graffiti, pigeon, swan and turkey. In another exemplary embodiment, the animal is a human.

In one exemplary embodiment, the microorganism is a member selected from a fungus and a yeast. In another exemplary embodiment, the fungus or yeast is an element selected from the species Candida, Trichophyton species, Microsporium species, Aspergillus species, Cryptococcus species, Blastomyces species, species

Cocciodioides, species Histoplasma, species

Paracoccidioides, Phycomycetes species, Malassezia species, Fusarium species, Epidermophyton species, species

Scytalidium species, Scopulariopsis species, Alternaria species, Penicillium species, Phialophora species, Rhizopus species, Scedosporium species and Zygomycetes species. In another exemplary embodiment, the fungus or yeast is an element selected from Aspergillus fumigatus (A fumigatus), Blastomyces dermatitidis, Candida Albicans (C. albicans, both susceptible and resistant fluconazole strains), Candida glabrata (C. glabrata ), Candida krusei (C. krusei),

Cryptococcus neoformans (C. neoformans), Candida parapsilosis, Candida tropicalis (C. 28 tropicalis), Cocciodiodes immitis, Epidermophyton floccosum (E. floccosum), Fusarium solani (F. solani), Histoplasma capsulatum, Malassezia furfur M. furfur), Malassezia pachydermatis (M. pachydermatis), Malassezia sympodialis (M. sympodialis), Microsporum audouinii (M. audouinii), Microsporum canis (M. canis), Microsporum gypseum (M. gypseum), Paracoccidioides brasiliensis and Phycomycetes spp , Trichophyton mentagrophytes (T. mentagrophytes), Trichophyton rubrum (T. rubrum), Trichophyton tonsurans (T. tonsurans). In another exemplary embodiment, the fungus or yeast is an element selected from Trichophyton concentricum, T. violaceum, T. schoenleinii, T. verrucosum, T. soudanense, Microsporum gypseum, M. equinum, Candida guilliermondii, Malassezia globosa, M. obtusa, M. restricta, M. slooffiae and Aspergillus flavus. In another exemplary embodiment, the fungus or yeast is a member selected from dermatophytes, Trichophyton, Microsporum, Epidermophyton and yeast-like fungi.

In one exemplary embodiment, the microorganism is a bacterium. In one exemplary embodiment, the bacterium is a gram-positive bacterium. In another exemplary embodiment, the gram-positive bacterium is a member selected from the species Staphylococcus, Streptococcus species, Bacillus species, Mycobacterium species, Corynebacterium species ('Propionibacterium species'), Clostridium species, Actinomyces species, Enterococcus species and Streptomyces species. In one exemplary embodiment, the bacterium is a gram-negative bacterium. In another exemplary embodiment, the gram-negative bacterium is a member selected from Acinetobacter species, Neisseria species, Pseudomonas species, Brucella species, Agrobacterium species, Bordetella species, Escherichia species, Shigelia species, Yersinia species, Salmonella species, species Klebsiella, Enterobacter species, Haemophilus species, Pasteurella species, Streptobacillus species, Esoteric species, Campylobacter species, Vibrio species and Helicobacter species. In another exemplary embodiment, the bacterium is an element selected from Propionibacterium acnes; Staphylococcus aureus; Staphylococcus epidermidis, Staphylococcus saprophyticus; Streptococcus pyogenes; Streptococcus agalactiae; Streptococcus pneumoniae; Enterococcus faecalis; Enterococcus faecium; Bacillus anthracis; Mycobacterium avium-intracellulare; Mycobacterium tuberculosis, Acinetobacter baumanii; Corynebacterium diphtheria; Clostridium perfringens; Clostridium botulinum; Clostridium tetani; Neisseria gonorrhoeae; Neisseria meningitidis; Pseudomonas aeruginosa; Legionella pneumophila; Escherichia coli; Yersinia pestis; Haemophilus influenzae; Helicobacter pylori; Campylobacter fetus; Campylobacter jejuni; Vibrio cholerae; Vibrio parahemolyticus; Trepomena pallidum; Actinomyces israelii; Rickettsia prowazekii; Rickettsia rickettsii; Chlamydia trachomatis; Chlamydia psittaci; Brucella abortus; Agrobacterium tumefaciens and Francisella tularensis.

In another exemplary embodiment, the microorganism is a bacterium that is a member selected from acid-resistant bacteria, including the Mycobacterium species; bacilli, including Bacillus species, Corynebacterium species (also Propionibacterium) and Clostridium species; filamentous bacteria, including the species Actinomyces and the Streptomyces species; bacilli, such as Pseudomonas species, Brucella species, Agrobacterium species, Bordetella species, Escherichia species, Shigella species, Yersinia species, Salmonella species, Klebsiella species, Enterobacter species, Haemophilus species, Pasteurella species and Streptobacillus species; squalene species, Campylobacter species, Vibrio species and intracellular bacteria including the Rickettsiae species and the Chlamydia species.

In an exemplary embodiment, the micro-organism is a virus. In an exemplary embodiment, the virus is a member selected from hepatitis AB, human rhinovirus, yellow fever virus, human respiratory coronavirus, Severe Acute Respiratory Syndrome (SARS), respiratory syncytial virus, influenza virus and parainfluenza 1-4, human immunodeficiency virus 1 (HIV-1), human immunodeficiency virus 2 (HIV-2), herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human cytomegalovirus (HCMV), varicella zoster virus, Epstein-Barr virus (EBV), polyvirus, coxsackie virus, ecovirus, rubella virus, neurodermatropic virus, smallpox virus, papovirus, rabies virus, dengue virus, Nile valley fever virus and SARS virus. In another exemplary embodiment, the virus is an element selected from picornaviridae, flaviviridae, coronaviridae, paramyxoviridae, orthomyxoviridae, retroviridae, herpesviridae and hepadnaviridae. In another exemplary embodiment, the virus is an element selected from a virus included in the following table:

Table A. Viruses

Virus Class Relevant Human Infections Viruses RNA Picornaviridae Polio Human hepatitis A 31

Human Rhinovirus Togaviridae and Flaviviri dae Rubella - German measles Yellow fever Coronaviridae Human respiratory corona virus (CVH) Severe acute respiratory syndrome (SAR) Rhabdoviridae Lissavlrus - Rabies Paramyxoviridae Paramo virus - Papeira Morbillvirus - measles Pneumovirus - respiratory syncytial virus Orthomyxoviridae Influenza AC Bunyavirus - Bunyamwera (BUN) Bunyaviridae Hantavirus - Hantaan (HTN) Nairevirus - Crimean-Congo Haemorrhagic Fever (CCHF) Flebovirus - Papatasii Fever (SFN) Uukuvirus - Uukuniemi (UUK) Rift Valley Fever (RVFN)

Virus Classes Relevant Human Infections RNA Virus Arenaviridae Junin - Argentina Haemorrhagic Fever Machupo - Bolivia Haemorrhagic Fever Lassa - Lassa Fever LCM - Aseptic Lymphocytic Choriomeningitis Reoviridae Rotovirus Reovirus Orbivirus 32

Retroviridae Human immunodeficiency virus 1 (HIV-1) Human immunodeficiency virus 2 (HIV-2) Human immunodeficiency virus Simia (VIS) DNA virus Papovaviri dae Kidney virus present in the kidney Virus class Relevant Human Infections Adenoviridae Human respiratory distress and some infections (HSV-1) Human herpes simplex Virus 1 (HSV-1) Human cytomegalovirus (HCMV) Varicella zoster virus (VZV) Epstein-Barr virus (EBV) ) Human herpes virus 6 (HHV6) Poxviridae Ortopoxvirus is subgenus of smallpox Hepadnaviridae Hepatitis B virus (HBV) Hepatitis C virus (HCV)

In one exemplary embodiment, the microorganism is a parasite. In an exemplary embodiment, the parasite is a member selected from Plasmodium falciparum, P. vivax, P. ovale P. malariae, P. berghei, Leishmania donovani, L.infantum, L. chagasi, L. mexicana, L. amazonensis, L. venezuelensis, L. tropics, L. major, L. minor, L. aethiopica, L. Biana braziliensis, L. (V.) guyanensis, L. (V.) panamensis, L. (V.) peruviana, Trypanosoma brucei rhodesiense, T. brucei gambiense, T. cruzi, Giardia intestinalis, G. lambda, Toxoplasma gondii, Entamoeba histolytica, Trichomonas vaginalis, Pneumocystis carinii and Cryptosporidium parvum. 33 V. Methods of Treatment or Prevention of Infections

Benzoxaborols having the structure disclosed herein may be used in a method of treating or preventing an infection or both. The method includes administering to the animal a therapeutically effective amount of the compound, sufficient to treat or prevent said infection. In an exemplary embodiment, the animal is a member selected from human, bovine, goat, pig, sheep, horse, cow, bull, dog, guinea pig, rabbit, rabbit, chicken, turkey. In another exemplary embodiment, the infection is a member selected from a systemic infection, a skin infection, and a nail or periungual infection. V. a) Methods of Treatment or Prevention of Ungual and / or Peri-Fluidal Infections

The benzoxaborols having the structures disclosed herein may be used in a method of treating or preventing a nail or periungual infection. The method includes administering to the animal a therapeutically effective amount of the compound, sufficient to treat or prevent said infection. In another exemplary embodiment, the method includes administering the compound of the invention to a site that is selected from skin, nail, hair, hoof, claw and skin surrounding the nail, hair, hoof and claw. V. a) 1) Onychomycosis Onychomycosis is a nail disease caused by yeast, dermatophytes or other molds and accounts for approximately 50% of all nail diseases. Infection of the foot nails 34 accounts for approximately 80% of the incidence of onychomycosis, while the nails of the hand are affected in about 20% of cases. Dermatophytes are the most frequent cause of invasion of the nail plate, particularly in onychomycosis of the nails of the foot. Onychomycosis caused by a dermatophyte is called Tinea unguium. The Trichophyton rubrum is by far the isolated dermatophyte most frequently, followed by T. mentagrophytes. Subungual distal onychomycosis is the most common form of presentation of Tinea unguium, the main site of entry through the hyponychium (the thicker epidermis under the free distal end of a fingernail) progressing over time to envelop bed and plaque nails The disease is characterized by discoloration, onycholysis and an accumulation of subungual waste and dystrophy of the nail plate. The disease adversely affects the quality of life of its victims, ranging from the complaints of the individual from the bad aspect of the nails and the discomfort caused by footwear, to more serious complications, including secondary bacterial infections.

Many methods of treating fungal infections are known, including or oral or topical use of antibiotics (eg, nystatin and amphotericin B), imidazole antifungal agents such as miconazole, clotrimazole, fluconazole, econazole and sulconazole, and antifungal agents different from imidazole, such as albylamine-derived terbinafine and naphthine, and butylamine from the benzylamine class.

However, onychomycosis has proven to be resistant to most treatments. Nail fungal infections are located in a difficult access zone by conventional topical treatment and antifungal drugs hardly penetrate the nail plate to reach the sites of infection under the nail. Therefore, onychomycosis has been commonly treated by oral administration of anti-fungal drugs; however, this is clearly undesirable because of the possible side effects of these drugs, in particular those caused by more potent antifungal drugs, such as itraconazole and ketoconazole. An alternative method of treatment of onychomycosis is to remove the nail prior to treatment with a topically active antifungal agent; this type of treatment is equally undesirable. Systemic antifungal agents require prolonged use and can have considerable side effects. Topical agents have usually been of little benefit, primarily because of the poor penetration of the anti-fungal agents into and through the nail volume.

This specification therefore discloses a method of treating or preventing onychomycosis. The method includes administering to the animal a therapeutically effective amount of a pharmaceutical formulation of the invention, sufficient to treat or prevent onychomycosis. In another exemplary embodiment, the method includes administering the pharmaceutical formulation of the invention to a site which is selected from skin, nail, hair, hoof, claw and skin surrounding the nail, hair, hull and jaw. V. a) 2) Other Ungual and Periungual Infections

The benzoxaborols having the structures disclosed herein may be used in a method of treating or preventing a nail or periungual infection in a mammal. This method includes administering to the mammal a therapeutically effective amount of said compound, thereby treating or preventing nail or periungual infection. In another exemplary embodiment, nail or periungual infection is a member selected from: chloronychia, paronychia, erysipeloid, onicorrex, gonorrhea, pool granuloma, larva migrans, leprosy, Orf nodule, milker's nodules, herpetic whitlow, perionate bacterial infections, acute bacterial, chronic perinatal, sporotrichosis, syphilis, verrucous cutaneous tuberculosis, tularémia, tunguiase, peri-and subungual warts, zona, nail dystrophy (trachyonychia) and nail dermatological diseases such as psoriasis, pustular psoriasis, alopecia Aerata, pustular parakeratosis, contact dermatosis, Reiter's syndrome, psoriasiform dermatitis of the extremities, lichen planus, idiopathic nail atrophy, lichen nevus, lichen striatus, necro epidermal inflammatory verrucous linear (NEVIL), alopecia, pemphigus, bullous pemphigus, epidermolysis bullosa acquired, Darier's disease, pityriasis rubra pilaris, keratoderma palmoplantaris, eczema polymorphic erythema, scabies, Bazex syndrome, systemic scleroderma, systemic lupus erythematosus, chronic lupus erythematosus, dermatomyositis.

Compounds and pharmaceutical formulations of the invention useful for nail and periungual applications also have application in the field of cosmetics, in particular in the treatment of nail irregularities, coilonychia, Beau lines, longitudinal grooves, ingrown nails.

In an exemplary embodiment, the infection is of the skin, nail, hair, claw or hoof, ear or eye and is a member selected from sporotrichosis, mycotic keratitis, surface oculomycosis, endogenous oculomycosis, lobomycosis, mycetoma, stone, tinea versicolor, It had the body, had crural, had the feet, had the beard, had 37 of the head, had nigra, otocomicose, had favosa, chromomycosis and had imbricata. V. b) Methods of Treatment of Systemic Diseases

The benzoxaborols having the structures disclosed herein may be used in a method of treating a systemic disease. The method involves causing the animal to contact said compound. The method of administration for the treatment of systemic diseases may be oral, intravenous or transdermal.

In an exemplary embodiment, the infection is systemic and is a member selected from candidiasis, aspergillosis, coccidioidomycosis, cryptococcosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, zygomycosis, faeohyphomycosis and rhinosporidiosis. V. c) Methods of Treatment of Diseases Involving Viruses

The compounds of the invention are useful for the treatment of diseases, both animal and human, involving viruses. In an exemplary embodiment, the disease is a member selected from hepatitis A-B-C, yellow fever, respiratory syncytial, influenza, AIDS, herpes simplex, varicella, varicella zoster and Epstein-Barr disease. V. (c) Methods of Treatment of Diseases Involving Parasites

The compounds of the invention are useful for the treatment of both animal and human diseases involving parasites. In an exemplary embodiment, the disease is a member selected from malaria, Chagas disease, leishmaniasis, African trypanosomiasis (African human trypanosomiasis), giardiasis, toxoplasmosis, amoebiasis, and cryptosporidiosis. SAW. Methods of Penetration in the Fingernail

A poor penetration of the active agent through the hock or nail plate and / or excessive binding to keratin (the main protein in the nails and hairs) is believed to be the reasons for the poor efficacy of cyclopirox, 8% w / w commercial varnish, and other topical treatments that have failed clinical trials. In cases of mild onychomycosis, the pathogenic fungi are located only in the nail plate. In moderate or severe cases, the pathogenic fungi are fixed in the nail plate and in the nail bed. If the infection has disappeared from the nail plate but not from the nail bed, the fungal pathogens may re-infect the nail plate. Therefore, in order to effectively treat onychomycosis, the infection must be eliminated from the nail plate and the nail bed. For this, the active agent has to penetrate and spread considerably through the nail plate and the nail bed.

It is believed that for an active agent to be effective once disseminated throughout the infected zone, it must be bioavailable to the fungal pathogens and can not be so firmly and / or preferably bound to keratin that it renders the drug inactive. Knowledge of the nail plate morphology suggests certain physico-chemical properties of an active agent that would facilitate penetration into the nail plate. The desired physico-chemical properties are fully described. The compounds of the present invention tested are capable of penetrating the nail plate and are also active against Trichophyton rubrum and mentagrophytes and other species. In addition, the compounds tested are also active against Trichophyton rubrum in the presence of 5% keratin powder. Also to be noted is a method of providing a compound of the dorsal layer of the nail plate to the nail bed. This method comprises contacting the cell with a compound capable of penetrating the nail plate under conditions sufficient to penetrate the nail. The compound is shown in the table below. OH Compound D (compound 2) Formula: c7h6bf2 c7h6bcy2 Molecular weight (Da): 151.93 168.39 Plasma protein binding (%): 66 83 Log P: 1.9 2.3 Solubility in water (g / ml):> 100> 100 Compound 3 below, which is outside the scope of the invention, is an example of a compound having a molecular weight similar to cyclopirox and the like which penetrates very little (%): 100 cLog P: 3.55 Solubility in water (g / mL): C13H10BFO Molecular weight (Da): 212.03 ): not determined The penetration of the active ingredient into the nail can be effected by the polarity of the formulation. However, the polarity of the formulation is not expected to have as much influence on nail penetration as other factors, such as molecular mass or Log P of the active ingredient. The presence in the formulation of penetration enhancing agents prov penetration of the active agent is increased in comparison with similar formulations which do not contain penetration enhancer.

This specification further discloses methods of treating a viral infection mediated, at least in part, by dermatophytes, Trichophyton, Microsporum or Epidermophyton species, or by a yeast-like background including the Candida species in mammals, with methods comprising administering to the mammal, to which said viral infection or at risk of contracting is diagnosed, a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound disclosed herein or mixtures of one or more of such compounds. In one embodiment, the infection is onychomycosis.

The benzoxaborols of the publication may have broad spectrum antifungal activity and as such may be candidates for use against other cutaneous fungal infections.

The methods referred to in this section are useful in penetrating the nails and hooves, as well as in the treatment of nail and periungual diseases. VII. Pharmaceutical formulations

In another aspect, the invention is a pharmaceutical formulation comprising: (a) a pharmaceutically acceptable excipient, and (b) a benzoxaborol having one of the structures disclosed herein. The formulation is intended for pharmaceutical use.

The pharmaceutical formulations of the invention may take a variety of forms adapted to the chosen route of administration. Those skilled in the art will consider various synthetic methodologies which may be used to prepare non-toxic pharmaceutical formulations incorporating the compounds described herein. Those skilled in the art will consider a wide variety of pharmaceutically acceptable solvents which may be used to prepare solvates of the compounds of the invention, such as water, ethanol, propylene glycol, mineral oil, vegetable oil and dimethylsulfoxide (DMSO).

The compositions of the invention may be administered orally, topically, parenterally, by inhalation or by spraying or rectally, in unit dose formulations containing non-toxic pharmaceutically acceptable carriers, adjuvants and carriers. It is further understood that the best method of administration may be a combination of methods. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troches, or the like is particularly preferred. The term parenteral as used herein includes subcutaneous injections, intradermal injection, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or similar infusion techniques or techniques.

The pharmaceutical compositions are preferably in a form suitable for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, granules or dispersible powders, emulsion, hard or soft capsules or syrups or elixirs.

Compositions intended for oral use may be prepared by any method known in the art for the manufacture of pharmaceutical formulations and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents to provide pleasant and pharmaceutically flavored. The tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for their manufacture. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, starch or alginic acid; binding agents, for example, starch, gelatin or gum arabic; and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide prolonged action over a long period. For example, a retarding substance such as glyceryl monostearate or glyceryl distearate may be used.

Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules, in which the active ingredient active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active substances admixed with suitable excipients for the manufacture of aqueous suspensions. These excipients are suspending agents, for example carboxymethylcellulose, methylcellulose, sodium hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tradacanth or gum arabic; and dispersing or wetting agents which may be a naturally occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of an ethylene oxide with aliphatic alcohols for example heptadecaethyleneoxycetanol, or condensation products of an ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono-oleate, or condensation products of an ethylene oxide with partial esters derived from of fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may further contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, or one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending active ingredients in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those listed above, and flavoring agents may be added to provide flavored oral preparations. These compositions may be preserved by the addition of an anti-oxidant agent such as ascorbic acid. Dispersible powders and granules suitable for preparing an aqueous suspension by addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring or coloring agents, may also be present.

The pharmaceutical formulations of the invention may also be in the form of oil-in-water emulsions and water-in-oil emulsions. The oil phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin, or mixtures thereof. Suitable emulsifying agents may be gums of natural origin, for example gum arabic or gum tragacanth; phosphatides of natural origin, for example soybean meal, lecithin, and esters or partial esters derived from fatty acids and hexitol; anhydrides, for example sorbitan monooleate; and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol sorbitol or sucrose. These formulations may also contain an emollient, a preservative and sweetening and flavoring agents. The pharmaceutical formulations may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to the known art using the dispersing or wetting agents and the suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butenediol. Acceptable carriers and solvents may be used water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as a solvent or suspension medium. For this, any light fixed oil may be used including mono- or diglycerides. In addition, fatty acids such as oleic acid are useful in the preparation of injectables. The composition of the invention may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at normal temperatures but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. These materials are cocoa butter and polyethylene glycols.

Alternatively, the compositions may be administered parenterally in a sterile medium. The drug, depending on the carrier and the concentration used, may be suspended or dissolved in the carrier. Advantageously, local analgesics, preservatives and buffering agents may be dissolved in the vehicle.

For administration to non-human animals, the composition containing the therapeutic compound may be added to the water or food of the animals. In addition, it will be convenient to formulate the rations and drinking water of the animals so that they ingest an appropriate amount of the compound in their diet. It will also be convenient to present the compound in a composition as a premix to be added to the food and water. A human food or beverage supplement may also be added to the composition. Dosage levels of the order of about 5 mg to about 250 mg per kilogram of body weight per day and more preferably about 25 mg to about 150 mg per kilogram of body weight per day are useful in the treatment of diseases above. The amount of active ingredient that can be combined with the carrier materials to produce a unit dosage form will depend on the disease being treated and the particular mode of administration. The unit dosage forms will generally contain from about 1 mg to about 500 mg of an active ingredient. The frequency of the shot may also vary depending upon the compound used and the specific disease treated. However, for the treatment of most conditions, a dosage regimen of 4 times a day or less is preferred. It is to be understood, however, that the specific dose level for a given patient will depend on a variety of factors including the activity of the specific compound used, age, body mass, general health, sex, diet, timing of administration, route of administration and rate of excretion, drug combination, and severity of the specific disease undergoing therapy. The half-life of the compound is inversely proportional to the frequency of taking a compound. In vitro, the half-lives of the compounds can be predicted from microsomal half-life assays as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127). The amount of the composition required for use in the treatment will vary not only with the specific compound selected, but also with the route of administration, the nature of the disease to be treated and the age and condition of the patient and will ultimately be at the discretion of the clinician or physician assistant. VII. a) Topical Formulations

In a preferred embodiment, the compounds of the publication can be used by topical application of the compounds.

The compositions of the present invention comprise semi-solid or fluid carriers which may include, but are not limited to, polymers, thickeners, buffers, neutralizers, chelating agents, preservatives, surfactants or emulsifiers, antioxidants, waxes or oils , emollients, sunscreens and a solvent or mixed solvent system. The solvent or mixed solvent system is important for the formation, because it is the first one responsible for the dissolution of the drug. The improved solvent or mixed solvent system is also capable of maintaining the clinically relevant levels of the drug in solution, despite the addition to the formation of a weak solvent. Topical compositions useful for the purpose of the invention may be produced in a wide variety of product types. These include, but are not limited to, lotions, creams, pencils for lesions, sprays, ointments, pastes, foams, mousses and cleansers. These product types may comprise various types of carrier systems including, but not limited to, particles, nanoparticles and liposomes. If desired, disintegrating agents such as crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof can be added as sodium alginate. Techniques for formulation and administration can be found in Remington: The Science and Practice of Pharmacy, supra. The formulation may be selected to maximize release at a desired target site in the body.

Lotions, which are preparations which are to be applied to the surface of the skin, nail, hair, claw or hull without friction, are typically liquid or semi-liquid preparations in which a finely divided, solid or liquid solid is dispersed. Lotions usually contain suspending agents to produce better dispersions, as well as compounds useful for fixing and maintaining the active agent in contact with the skin, nail, hair, claw or hull, e.g., methylcellulose, sodium carboxymethylcellulose or the like.

The creams containing the active agent to be released according to the invention are viscous liquids or semi-solid emulsions, both oil-in-water and water-in-oil. The cream bases are washable with water and contain an oily phase, an emulsifier and an aqueous phase. The aqueous phase is generally comprised of petroleum jelly or a fatty alcohol, such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oily phase by volume and generally contains a humectant. The emulsifier in a cream formulation, as explained in Remington: The Science and Practice of Pharmacy, supra, is generally a nonionic, anionic, cationic or amphoteric surfactant.

Gel formulations may also be used in the perspective of the present invention. As will be appreciated by those working in the field of topical drug formulation, the gels are semi-solid. Single phase gels contain macromolecules distributed substantially evenly throughout the liquid carrier, which is typically aqueous, but may also be a solvent or mixture of solvents.

Ointments, which are semi-solid preparations, are typically based on petrolatum or other petroleum derivatives. As will be appreciated by the skilled person, the specific ointment base to be used is one which provides optimum release of the active agent chosen for a given formulation and, preferably, also provides other characteristics, e.g., emollient property or the like. As with other carriers or carriers, an ointment base must be inert, stable, non-irritating and non-sensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, Pa .: Mack Publishing Co., 1995), pages 1399-1404, ointment bases can be grouped into four classes: oil bases; emulsifiable bases; emulsifying bases and water-soluble bases. Oil ointment bases include, for example, vegetable oils, animal fats and semi-solid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxy stearine sulfate, anhydrous lanolin and hydrophilic vaseline. Emulsifying ointment bases are water-in-oil (A / O) emulsions or oil-in-water (O / W) emulsions and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of various molecular weights; Again, reference may be made to Remington: The Science and Practice of Pharmacy, supra, for more information.

Also useful formulations of the invention include sprays. Generally, sprays provide the active agent in an aqueous and / or alcoholic solution that may be vaporized on the skin, nail, hair, claw or hull to release the active agent. These sprays include those formulated to provide a concentration of the solution of the active agent at the site of administration following the release, eg, the powdered solution may be primarily composed of alcohol or other similar volatile liquids in which the drug or active agent may be dissolved. Upon release into the skin, nail, hair, claw or hull, the carrier evaporates, leaving the active agent concentrated at the site of administration. 51

The topical pharmaceutical compositions may further comprise suitable gel or solid phase supports. Examples of such carriers include, but are not limited to, sodium carbonate, sodium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols.

The topical pharmaceutical compositions may further comprise a suitable emulsifier which refers to an agent which enhances and facilitates the mixing and suspension of oil-in-water or water-in-oil. The emulsifying agent used herein consists of a single emulsifying agent or may be a nonionic, anionic, cationic or amphoteric surfactant or mixture of one or two such surfactants; the nonionic or anionic emulsifiers are preferred for use herein. These surface active agents are described in " McCutcheon's Detergent and Emulsifiers, " North American Edition, 1980 Yearbook published by McCutcheon Division, MC Publishing Company, 175 Rock Road, Glen Rock, N.J. 07452, USA.

Preferred for use herein are high molecular weight alcohols such as cetearyl alcohol, cetyl alcohol, stearyl alcohol, emulsifying wax, glyceryl monostearate. Other examples are ethylene glycol distearate, sorbitan tristearate, propylene glycol monostearate, sorbitan monooleate, sorbitan monostearate (SPAN 60), diethyleneglycol monolaurate, sorbitan monoplamate, sucrose dioleate, sucrose stearate (CRODESTA F-160) (BRIJ 32), polyoxyethylene stearyl ether (21) (BRIJ 721), polyoxyethylene monostearate (Myrj 45), polyoxyethylene 52 sorbitan monostearate (TWEEN 60), polyoxyethylene lauryl ether (BRIJ 30), polyoxyethylene ), polyoxyethylene sorbitan monooleate (TWEEN 80), polyoxyethylene sorbitan monolaurate (TWEEN 20) and sodium oleate. Cholesterol and cholesterol derivatives can also be used in external emulsions and promote o / w emulsions.

Especially suitable nonionic emulsifying agents are those having hydrophilic-lipophilic equilibria (HLB) of from about 3 to 6 to 1% or to 8 to 18%, as determined by the method described by Paul L. Lindner in " Emulsions and Emulsion " organized by Kenneth Lissant, published by Dekker, New York, NI, 1974, pages 188-190. More preferred for use herein are one or more nonionic surfactants which produce a system having HLB of from about 8 to about 18.

Examples of such nonionic emulsifiers include, but are not limited to, " BRIJ 72 ", the trade designation of polyoxyethylene (2) stearyl ether having an HLB of 4.9; " BRIJ 721 ", the trade designation of polyoxyethylene (21) stearyl ether having an HLB of 15.5; " Brij 30 " the commercial designation of polyoxyethylene lauryl ether having a HLB of 9.7; " Polawax ", the commercial designation of emulsifying wax having an HLB of 8.0; " Span 60 ", the trade designation of sorbitan monostearate having an HLB of 4.7; " Crodesta F-160 ", the trade designation of sucrose stearate having a HLB of 14.5. All these materials are available from Ruger Chemicals Inc .; Croda; ICI Americas, Inc .; Spectrum Chemicals and BASF. When the topical formulations of the present invention contain at least one emulsifying agent, each emulsifying agent is present in an amount of about 0.5 to about 2.5% m, preferably 0.5 to 2.0%, more preferably 1% , 0% or 1.8%. Preferably the emulsifying agent comprises a mixture of stearet 21 (at about 1.8%) and stearet 2 (at about 1.0%).

The topical pharmaceutical compositions may further comprise suitable emollients. Emollients are materials used for preventing or relieving dryness, as well as for protecting the skin, nail, hair, claw or helmet. Useful emollients include, but are not limited to, cetyl alcohol, isopropyl myristate, stearyl alcohol and the like. There is a great variety of emollients that can be used here. See e.g., Sagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp. 32-43 (1972) and U.S. Pat. No. 4,919,934, to Deckner et al., Issued January 24, 1990, both fully incorporated herein by reference. These materials are available from Ruger Chemical Co., (Irvington, NJ).

When the topical formulations of the present invention contain at least one emollient, each emollient is present in an amount of about 0.1 to 15%, preferably 0.1 to about 3.0, more preferably 0.5, 1.0 and 2.5% m. Preferably, the emollient is a mixture of cetyl alcohol, isopropyl myristate and stearyl alcohol in a 1/5/2 ratio. The emollient may also be a mixture of cetyl alcohol and stearyl alcohol in a 1/2 ratio.

Topical pharmaceutical compositions may also comprise suitable antioxidants, substances known to inhibit oxidation. Antioxidants suitable for use in accordance with the present invention include, but are not limited to butylated hydroxytoluene, ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbic palmitate, butylated hydroxyanisole, 2,4,5-trihydroxybutyrofen, 4- hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, guaiac gum, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butyl hydroquinone and tocopherols such as vitamin E and the like, including salts and esters f pharmaceutically acceptable salts of such compounds. Preferably, the antioxidant is butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, its pharmaceutically acceptable salts and esters or mixtures thereof. Most preferably, the antioxidant is butylated hydroxytoluene. These materials are available from Ruger Chemical Co., (Irvington, NJ).

When the topical formulations of the present invention contain at least one antioxidant, the total amount of antioxidant present is about 0.001 to 0.5% m, preferably 0.05 to about 0.5% m, more preferably 0.1%

Topical pharmaceutical compositions may also comprise suitable preservatives. Preservatives are compounds added to the pharmaceutical formulation to act as an antimicrobial agent. Among preservatives known in the art as effective and acceptable in parenteral formulations are benzalkonium chloride, benzethonium, chlorhexidine, phenol, m-cresol, benzyl alcohol, methylparaben, propylparaben, chlorobutanol, o-cresol, p-cresol, chlorocresol, nitrate phenylmercuric, thimerosal, benzoic acid and various mixtures thereof. See, e.g., Wallhausser, K.-H., Develop. Biol. Standard, 24: 9-28 (1974) (S. Krager, Basel). Preferably, the preservative is selected from methylparaben, propylparaben and mixtures thereof. These materials are available from Inolex Chemical Co. (Philadelphia, PA) or Spectrum Chemicals. 55

When the topical formulations of the present invention contain at least one preservative, the total amount of preservative present is about 0.01 to 0.5% m, preferably 0.1 to about 0.5% m, more preferably about from 0.03 to about 0.15. Preferably, the preservative is a mixture of methylparaben and propylparaben in a 5/1 ratio. When alcohol is used as a preservative, the amount is usually 15 to 20%.

Topical pharmaceutical compositions may also comprise chelating agents suitable for forming metal cation complexes that do not cross the lipid double layer. Examples of suitable chelating agents include ethylenediamine tetraacetic acid (EDTA), ethylene glycol bis (beta-aminoethyl) -α, Ν, Ν ', N'-tetraacetic acid (EGTA) and 8-amino-2- [(2-amino-5-methylphenoxy) methyl] -6-methoxyquinoline-N, N ', N'-tetraacetic acid, tetrapotassium salt (QUIN-2). Preferably, the chelating agents are EDTA and citric acid. These materials are available from Spectrum Chemicals.

When the topical formulations of the present invention contain at least one chelating agent, the total amount of chelating agent present is from about 0.005 to 2.0% by weight, preferably from about 0.05 to about 0.5% more preferably about 0.1% m.

The topical pharmaceutical compositions may also comprise suitable neutralizing agents used to adjust the pH of the formulation to the pharmaceutically acceptable range. Examples of suitable neutralizing agents include, but are not limited to, trolamine, tromethamine, sodium hydroxide, hydrochloric acid, citric acid and acetic acid. These materials are available from Spectrum Chemicals (Gardena, CA).

When the topical formulations of the present invention contain at least one neutralizing agent, the total amount of neutralizing agent present is from about 0.1 to about 10% m, preferably 0.1 to about 5.0% and more preferably about of 1.0% m. The neutralizing agent is generally added in the amounts necessary to bring the formulation to the desired pH.

Topical pharmaceutical compositions may also comprise suitable viscosifying enhancing agents. These compounds are diffusible compounds capable of increasing the viscosity of a solution containing polymer through the interaction of the agent with the polymer. CARBOPOL ULTREZ 10 may be used as viscosity enhancer. These materials are available from Noveon Chemicals, Cleveland, OH.

When the topical formulations of the present invention contain at least one viscosity enhancing agent, the total amount of viscosity enhancing agent present is from about 0.25% to about 5.0% by weight, preferably from about 0.25% % to about 1.0% and more preferably from about 0.4% to about 0.6% m.

Topical pharmaceutical compositions may also comprise suitable nail penetration enhancers. Examples of such nail penetration enhancers include mercaptan, sulfide and bisulfide compounds, keratolytic agents and surfactants. Nail penetration enhancers suitable for use in the invention are described in Malhotra et al., J. 57

Pharm. Sci., 91: 2, 312-323 (2002), hereby fully incorporated by reference.

The topical pharmaceutical compositions may also comprise one or more suitable solvents. The ability of any solid substance (solute) to dissolve in any liquid substance (solvent) depends on the physical properties of the solute and the solvent. When solutes and solvents have similar physical properties, the solubility of the solute in the solvent will be maximal. This raises the traditional perception that " similar dissolves similar ". The solvents may be characterized at one end as non-polar, lipophilic oils, while at the other end they are polar hydrophilic solvents. Oily solvents dissolve other non-polar substances by Van der Wals attractions, while water and other hydrophilic solvents dissolve polar substances by dipole ionic interactions or hydrogen bonds. All solvents may be listed continuously from the least polar, i.e. hydrocarbons such as decan to the more polar which is water. A solute will have its maximum solubility in solvents with equivalent polarity. Thus, for drugs with a minimum solubility in water, less polar solvents provide greater solubility; the solvent having a polarity equivalent to that of the solute provides the maximum solubility. Most drugs have an intermediate polarity and therefore, maximum solubility in solvents such as propylene glycol or ethanol, which are considerably less polar than water. If the drug has higher solubility in propylene glycol (eg 8% (m / m)) than in water (eg 0.1% (m / m)) then adding water to propylene glycol leads to a reduction in the maximum value of solubility of the drug in the solvent mixture compared to pure propylene glycol. Addition of a weak solvent to an excellent solvent will decrease the maximum solubility in the blend compared to the maximum solubility in the excellent solvent.

When incorporating compounds into topical formulations, the concentration of the active ingredient in the formulation may be limited by its solubility in the chosen solvent and / or carrier. Non-lipophilic drugs usually show very low solubility in solvents and / or pharmaceutically acceptable carriers. For example, the water solubility of some compounds of the invention is less than 0.00025% m / m. The solubility of such compounds of the invention may be less than about 2% m / m in both propylene glycol and isopropyl myristate. In one embodiment of the present invention, diethyleneglycol monoethyl ether (DGME) is the solvent used to dissolve the compounds of Formula (I) and Formula (II). It is believed that the compounds of the invention useful in the present formulation have a solubility from about 10% m / m to about 25% m / m in DGME. In another embodiment a DGME-water co-solvent system is used to dissolve the compounds of Formula (I) and Formula (II). The solvent capacity of the DGME drops when water is added; however, the DGME-water co-solvent system can be designed to maintain the desired concentration of about 0.1% to about 5% w / w active ingredient. Preferably, the active ingredient is present at about 0.5% to about 3% w / w and more preferably at about 1% w / w in the topical formulations at the time of application. Because DGME is less volatile than water, when the topical formulation evaporates upon application, the active ingredient becomes more soluble in the cream formulation. Higher solubility reduces the likelihood of reduced bioavailability caused by precipitation of the drug on the surface of the skin, nail, hair, claw and helmet.

Liquid forms, such as lotions, suitable for topical administration or suitable for cosmetic application may include a suitable aqueous or non-aqueous carrier with buffers, suspending or dispersing agents, thickeners, penetration enhancers and the like. Solid forms, such as creams or pastes or the like, may include, for example, any of the following ingredients, water, oil, alcohol or fat as a surfactant substrate, polymers such as polyethylene glycol, solid thickeners and the like. Liquid or solid formulations may include improved release technologies, such as liposomes, microsomes, microsponges and the like.

In addition, the compounds may be released using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various controlled release materials have been defined, and well known to those skilled in the art.

The topical treatment regimens according to the practice of this invention comprise applying the composition directly to the skin, nail, hair, claw and hull at the application site one or several times a day.

The formulations of the present invention may be used to treat, ameliorate or prevent diseases or symptoms associated with bacterial infections, acne, inflammation and the like.

In an exemplary embodiment, the pharmaceutical formulation includes a single solution. In exemplary embodiment, the simple solution includes an alcohol. In an exemplary embodiment, the simple solution includes alcohol and water. In an exemplary embodiment, the alcohol is ethanol, ethylene glycol, propanol, polypropylene glycol, isopropanol or butanol. In an exemplary embodiment, the simple solution is an element selected from about 10% polypropylene glycol to about 90% ethanol; about 20% polypropylene glycol and about 80% ethanol; about 30% polypropylene glycol and about 70% ethanol; about 40% polypropylene glycol and about 60% ethanol; about 50% polypropylene glycol and about 50% ethanol; about 60% polypropylene glycol and about 40% ethanol; about 70% polypropylene glycol and about 30% ethanol; about 80% polypropylene glycol and about 20% ethanol; about 90% polypropylene glycol and about 10% ethanol.

In an exemplary embodiment, the pharmaceutical formulation is a varnish. For more information on the production of varnishes please see Remington, supra.

In an exemplary embodiment, the compound is present in said pharmaceutical formulation in a concentration of about 0.5% to about 15%. In an exemplary embodiment, the compound is present in said pharmaceutical formulation in a concentration of about 0.1% to about 12.5%. In an exemplary embodiment, the compound is present in said pharmaceutical formulation in a concentration of about 1% to about 10%. In an exemplary embodiment, the compound is present in said pharmaceutical formulation in a concentration of about 1% to about 5%. In an exemplary embodiment, the compound is present in said pharmaceutical formulation in a concentration of about 2% to about 8%. In exemplary embodiment, the compound is present in said pharmaceutical formulation in a concentration of about 4% to about 9%. VII. b) Supplementary Active Agents

The following agents are examples of cosmetic and pharmaceutical agents that may be added to the topical pharmaceutical formulations of the present invention. The following agents are known compounds and are readily available as trade.

Anti-inflammatory agents include, but are not limited to, bisabolol, mentholate, dapsone, aloe, hydrocortisone, and the like.

Vitamins include, but are not limited to, Vitamin B, Vitamin E, Vitamin A, Vitamin D and the like and vitamin derivatives such as tazoretene, calcipotriene, tretinoin, adapalene and the like.

Anti-aging agents include, but are not limited to, niacinamide, retinol and retinoid derivatives, AHA, ascorbic acid, lipoic acid, coenzyme Q 10, beta-hydroxyacids, salicylic acid, copper bonding peptides, dimethylaminoethyl (DAEA) and the like.

Sunscreens and sunburn relief agents include, but are not limited to, PABA, jojoba, aloe, Padimate O, methoxycinnamates, proxamine HCL, lidocaine and the like. Self-tanning agents include, but are not limited to, dihydroxyacetone (DHA). 62

Psoriasis treatment agents and / or acne treatment agents include, but are not limited to, salicylic acid, benzoyl peroxide, tar, selenium sulfide, zinc oxide, pyrithione (zinc and / or sodium), tazoretene, calcipotriene, tretinoin, adapalene and the like.

Effective agents for controlling or modifying keratinization including, without limitation: tretinoin, tazoretene and adapalene.

The compositions comprising a compound / agent active from the publication and, optionally, at least one of these additional agents, is intended for topical application. In a first application, this leads to the compounds of the invention and any other active agent acting on, and treating, the skin, nail, hair, claw and helmet. Alternatively, any topically applied active agent may also be delivered systemically by transdermal routes.

In such compositions, a supplementary cosmetic or pharmaceutically effective agent, such as an inflammatory agent, vitamin, anti-aging agent and / or acne treatment agent, for example, is usually a minor component (from about 0.001% to about 20%). by weight or preferably from about 0.01% to about 10% by mass), the balance being various carriers or carriers and processing aids useful to produce the desired pharmaceutical form. VII. c) Tests

Preferred compounds for use in the present invention will have certain pharmacological properties. Such properties include, but are not limited to, low toxicity, poor binding to serum proteins, and desirable in vitro and in vivo half-lives. Assays used to predict bioavailability include transport across human intestinal monolayers, including Caco-2 cell monolayers. Serum protein binding may be predicted by albumin binding assays. These tests are described in an article by Oravcova et al. (1996, J. Chromat.B677: 1-27). The half-life of a compound is inversely proportional to the frequency of its administration. The half-lives of an in vitro compound can be predicted by means of microsome half-life assays as described by Kuhnz and Gleschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127). The toxicity and therapeutic efficacy of these compounds can be determined by standard pharmaceutical procedures in cell cultures or guinea pigs, eg, to determine LD50 (the dose lethal to 50% of the population) and ED50 (the dose therapeutically effective in 50% of the population ). The dose ratio between toxic and therapeutic effects constitutes the therapeutic index and may be expressed as the ratio of LD50 to ED50. Compounds having high therapeutic indexes are preferred. Data obtained in these cell culture assays and animal studies may be used in the formulation of a dosage range for use in humans. The dosage of these compounds is preferably contained within the range of concentrations in the circulation which includes ED50 with little or no toxicity. The dosage may vary in this range depending on the therapeutic form and route of administration used. The exact formulation, route of administration and dosage may be chosen by the physician in the face of the patient's disease. 64 (See, e.g., Fingi et al., 1975, " The Pharmacological

Basis of Therapeutics ", Ch. 1, p. 1). VII. d) Administration

The therapeutically effective dose can be initially estimated from cell culture assays, as disclosed herein. For example, the dose may be formulated in animal models to achieve the range of concentrations in the circulation which includes ED50 (dose effective to greater than 50%), as determined in cell culture, ie, the concentration of the tested compound reaching a inhibition of half the maximum bacterial cell growth. This information may be used to more accurately determine useful doses in humans.

In general, the compounds prepared by the methods, and from the intermediates, described herein will be administered in a therapeutically or cosmetically effective amount by any of the modes of administration of agents adopted for similar purposes. It is to be understood, however, that the specific dose level for a given patient will depend upon a variety of factors including the activity of the specific compound used, age, body mass, general health, sex, diet, timing of administration, route of administration, administration and rate of excretion, drug combination, severity of the particular disease undergoing therapy and the judgment of the prescribing physician. The drug may be administered once or twice daily or up to 3 or 4 times per day. The amount and range of administration may be individually adjusted to provide plasma active fraction levels that are sufficient to maintain the inhibitory effects of bacterial cell growth. Common dosages for systemic administration to a patient are in the range of 0.1 to 100 mg / day, preferably 1-500 mg / day, more preferably 10-200 mg / day, even more preferably 100-200 mg / day. Secured in terms of the surface areas of the patient's body, the usual dosages are in the range of 50-91 mg / m 2 / day. The amount of the compound in the formulation may vary within the full range used by the person skilled in the art. Typically, the formulation will contain, on a weight percent basis (% m), about 0.01-10% m of the drug based on the total formulation, the remainder being one or more pharmaceutically acceptable excipients. Preferably, the compound is present at a level of about 0.1-3.0% m, more preferably about 1.0% m. The invention is further illustrated by the following Examples. The Examples are not intended to define or limit the scope of the invention.

EXAMPLES Proton NMR is recorded on a Varian AS 300 spectrometer and chemical shifts are referred to as δ (ppm) from tetramethylsilane. Mass spectra are determined in Micromass Quattro II. EXAMPLE 1

Preparation of I from 4 via 5 1.1 Introduction of metal and boron 66

To a solution of 4 (17.3 mmol) in anhydrous THF (80 mL) at -78 ° C under nitrogen, tert-BuLi or n-BuLi (11.7 mL) was added dropwise and the solution It's brown. Then B (OMe) 3 (1.93 mL, 17.3 mmol) was injected all at once and the cooling bath was removed. The mixture was heated gradually with stirring for 30 min and then stirred in a water bath for 2 h. After addition of 6N HCl (6 mL), the mixture was stirred overnight at ambient temperature and about 50% hydrolysis occurred as shown in the TLC analysis. The solution was evaporated on a rotary evaporator and the residue was dissolved in MeOH (50 mL) and 6N HCl (4 mL). The solution was refluxed for 1 h and the hydrolysis was complete as indicated by TLC analysis. Rotary evaporation gave a residue which was dissolved in EtOAc, washed with water, dried and then evaporated. The crude product was purified by flash column chromatography over silica gel to give a solid of 80% purity. The solid was further purified with hexane to provide 7.2 mmol of I. 1.2 Results

The analytical data for the exemplary compounds of structure I are given below. 1.2. 5-Chloro-1,3-dihydro-1-hydroxy-2, 2-benzoxaborol (Cl) M.p. 142-150Â ° C. MS (ESI): m / z = 169 (M + 1, positive) and 167 (M-1, negative). HPLC (220 nm): 99% purity. 1H NMR (300 MHz, DMSO-d6): δ 9.30 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.38 d, J = 7.8Hz, 1H) and 4.96 (s, 2H) ppm. 1.2. b 1,3-Dihydro-5-fluoro-1-hydroxy-2.1-benzoxaborol (C10) 67 M.P. 110-114Â ° C. ESI MS: m / z = 150.9 (M-1). 1 H NMR (300 MHz, DMSO-d 6): δ 9.20 (s, 1H), 7.73 (dd, J1 = 6Hz, J2 = 6Hz, 1H), 7.21 (m, , 14 (m, 1H), 4.95 (s, 2H) ppm. EXAMPLE 2

Preparation of I from 2 via 6 2.1 Addition of Boron, Catalytic Reduction and Cyclization

A mixture of 2 (10.0 mmol), bis (pinacolato) diboron (2.79 g, 11.0 mmol), PdCl 2 (dppf) (250 mg, 3 mol%) and potassium acetate 94 g, 30.0 mmol) in 1,4-dioxane (40 mL) at 80 ° C overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The crude product was dissolved in tetrahydrofuran (80 mL), then sodium periodate (5.56 g, 26.0 mmol) was added. After stirring at room temperature for 30 min, 2N HCl (10 mL) was added and the mixture was stirred at ambient temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with ether to provide 6.3 mmol of the corresponding boronic acid. To a solution of the obtained boronic acid (0.595 mmol) in methanol (5 mL) was added sodium borohydride (11 mg, 0.30 mmol) and the mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give 0.217 mmol of I. 2.2 Results

The analytical data for the exemplary compounds of structure I are given below: 1.2.a. 1,3-Dihydro-5-fluoro-1-hydroxy-2.1-benzoxaborol (C10)

The analytical data of this compound are listed in 1.2.b. EXAMPLE 3

Preparation of I from 3 3.1 Addition of Boron and Cyclization in a Single Reactor

To a solution of 3 (4.88 mmol) and triisopropyl borate (1.35 mL, 5.86 mmol) in tetrahydrofuran (10 mL), n-butyl lithium (1, 6 mol / L in hexanes, 6.7 mL, 10.7 mmol) was added dropwise over 15 min at -78 ° C under a nitrogen atmosphere, and the mixture was stirred for 2 h while leaving warm to room temperature. The reaction was quenched with 2N HCl and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography and treated with pentane to give 0.41 mmol of I. 3.2 Results 69

The analytical data for the exemplary compounds of structure I are given below. 3.2.a 1,3-Dihydro-5-fluoro-1-hydroxy-2.1-benzoxaborol (C10)

The analytical data of this compound are listed in 1.2.b. EXAMPLE 4

Preparation of I from 3 3.1 Addition of Boron and Cyclization in a Single Reactor with Distillation

To a solution of 3 (4.88 mmol) in toluene (20 mL), triisopropyl borate (2.2 mL, 9.8 mmol) was added and the mixture was refluxed for 1 h. The solvent, the isopropyl alcohol generated and the excess triisopropyl borate were removed under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL) and cooled to -78 ° C. N-Butyllithium (3.2 mL, 5.1 mmol) was added dropwise over 10 min and the mixture was stirred for 1 h while allowing to warm to room temperature. The reaction was quenched with 2N HCl and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography to give 1.54 mmol of I. 4.2 Results

The analytical data for exemplary compounds of structure I are given below: 4.2.a. 1,3-Dihydro-5-fluoro-1-hydroxy-2, 2-benzoxaborol (C10)

The analytical data of this compound are listed in 1.2.b. EXAMPLE 5

Formulation

The compounds of the publication may be administered to a patient using a therapeutically effective amount of one of said compounds in any of the following three varnish formulations and a solvent formulation. The varnish formulation provides good durability while the solvent formulation provides good ease of use. The compounds may be applied using a spray formulation, paint varnish, drops or the like. 1. 20% propylene glycol; 70% ethanol; 10% compound of the invention; 2. 70% ethanol; 20% poly (vinylmethyl ether-alt-maleic acid monobutyl ester); 10% compound of the invention; 3. 56% ethanol; 14% water; 15% poly (2-hydroxyethyl methacrylate); 5% dibutyl sebacate; 10% compound of the invention; 4. 55% ethanol; 15% ethyl acetate; 15% polyvinyl acetate; 5% dibutyl sebacate; 10% compound of the invention. The preparation of these formulations is well known in the art and is found in references such as Remington: The Science and Practice of Pharmacy, supra. EXAMPLE 6

Anti-fungal CIM assays

All CIM assays followed the guidelines of the National Committee for Clinical Laboratory Standards (NCCLS) for anti-microbial assays of yeast and filamentous fungi (Pfaller et al., NCCLS publication M38-A - Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous (Nakamura, et al., Antimicrobial Agents And Chemotherapy, 2000, 44 (8)), which were incubated in a urea broth (Nakamura et al. ) 2185-2186) The results of the MIC tests are shown in FIG.

Keratin Assay

Many anti-fungal agents bind strongly to keratin, which not only reduces their antifungal potency, but can also restrict their penetration into the nail. The affinities of the compounds for the powdered keratin were determined by the method described in Tatsumi, Antimicrobial Agents and Chemotherapy, 46 (12): 3797-3801 (2002).

It is shown in FIG. 1 a comparison of MIC data for Cl and CIO compounds against T. rubrum, with and without the presence of 5% keratin. Anti-Fungal Activity Spectrum 0 (CIO) is a novel compound under development for use as topical antifungal treatment. The objective of this study was to determine the minimum inhibitory concentration (MIC) of (CIO) against 19 strains of fungi assay, including: Aspergilus fumigatus (A. fumigatus), Candida Albicans (C. albicans, both sensitive and resistant strains Candida parapsilosis), Candida parapsilosis (Candida parapsilosis), Candida parapsilosis (Candida parapsilosis), Cryptococcus neoformans (C.

Candida tropicalis (C. tropicalis), Epidermophyton floccosum (E. floccosum), Fusarium solani (F. solani), Malassezia furfur (M. furfur), Malassezia pachydermatis (M. pachydermatis), Malassezia sympodialis (M. sympodialis), Microsporum audouinii (M. audouinii), Microsporum canis (M. canis), Microsporum gypseum (M. gypseum), Trichophyton mentagrophytes (T. mentagrophytes), Trichophyton rubrum (T. rubrum), Trichophyton tonsurans (T. tonsurans). Fungal growth was assessed after exposure to various concentrations of (C10). In addition, the MIC (CIO) against T. rubrum was determined in the presence of 5% keratin powder and the minimal fungicidal concentration (CFM)

against T. rubrum and T. mentagrophytes. Cyclopirox and / or terbinafine and / or fluconazole and / or itraconazole were used as comparison elements and were similarly tested. These studies were performed in NAEJA

Pharmaceutical, Inc. Materials and Methods 73 (C10) was obtained from Anacor Pharmaceuticals, Inc. (Paio Alto, CA, USA). ATCC strains were obtained at ATCC (Manassas, VA, USA). Cyclopiroxolamine was obtained from Sigma-Aldrich Co. (St. Louis, MO, USA). Terbinafine, fluconazole, and itraconazole have been synthesized in NAEJA Pharmaceutical Inc. (Edmonton, AB, Canada), experimental procedures and analytical data for these standards are stored in the NAEJA files.

All CIM assays follow the guidelines of the National Committee for Clinical Laboratory Standards (NCCLS) for antimicrobial assays of yeast and filamentous fungi (Pfaller et al., 2002), except for the Malassezia species which was incubated in a urea broth Nakamura et al., 2000). The broth microdilution test was used to test the in vitro activity of (C10) against the 19 fungal strains of the assay. Briefly, the compounds were dissolved in DMSO and diluted in sterile water to give a working solution. Serial double dilutions of the working solution were prepared in 96-well plates and medium was added. The medium was RPMI, RPMI + MOPS, modified RPMI or modified urea broth. The plates were inoculated with fungal suspensions to give a final inoculum with 0.5-2.5 x 103 cells / ml for yeast or 0.4-5 x 104 CFU / ml for filamentous fungi and then incubated with 24- 168 h at 35 ° C. The final concentration of DMSO did not exceed 5%. MIC was defined as the lowest concentration which caused more than 90% reduction in growth, compared to the control without drug. CFM was defined as the lowest concentration which killed more than 90% of the fungi, compared to the control without drug.

Results and Conclusions 74

They are shown in FIG. 2 the results for MIC (CIO) and reference compounds against 19 fungal strains. They are shown in FIG. 2 the results for CFM of AN2690 against 2 fungal strains. 0 (CIO) have MIC values between 0.25 - 2 μg / mL against all fungi tested. Addition of 5% keratin powder in the medium does not affect MIC against T. rubrum. O (CIO) has a fungicidal activity against T. rubrum and T. mentagrophytes, with CFM values of 8 and 16 μg / mL, respectively. The reference compounds have MIC values in the range defined by NCCLS. EXAMPLE 9

Determination of Solubility, Stability and Log P of compounds of the present invention by LC / MS / MS

The solubility, the room temperature stability and the CIO Log P were determined by the following methodology.

Reagents and Standards:

Ethanol: Degree ACS 200 proof (EM Science, Gibbstown, NJ, USA); Octanol: Octyl alcohol (EM Science, Gibbstown, NJ, USA); Acetonitrile: HPLC Grade (Burdick & Jackson, Muskegon, MI, USA); Ammonium acetate: lot 3272X49621 (Mallinckrodt,

Phillipsburg, NJ, USA); CIO: lot A032-103 (Anacor Pharmaceuticals, Paio Alto, CA, USA); p-Nitrophenol (PNP): lot OGNO1 (TCI America, Portland, OR, USA); Water: Deionized water (from Millipore systems, Billerica, MA, USA,

Solubility The n-octanol and water were mutually pre-saturated by vigorously stirring a mixture of the two solvents 75 for a maximum of 12 hours and the mixture was allowed to separate. Solubility in each solvent was determined by adding 10 μl of 20, 40, 200, 1000 and 5000 μρ / πΛ of CIO in DMSO to pre-saturated n-octanol or water. After stirring the vortex sample for 10 s, the sample was centrifuged for 10 min at ca. 3000 rpm. A visual inspection was performed to determine whether the sample was clear or whether a granule had formed at the bottom of the tube.

Log P

CIO (10 μl of 5000 μg / ml) was added at 2X the final concentration to 0.5 mL of pre-saturated n-octanol and mixed. An equal volume (0.5 mL) of pre-saturated water was added, vortexed and then on a rotary shaker for one hour and 24 h in triplicate at ca. 25 ° C. The organic and aqueous layers were separated by centrifugation for 5 min at ca. 2000 rpm. 25 μl of the (top) layer of octanol was removed and placed in a labeled tube. 25 μl of the aqueous (lower) layer was removed, taking care to avoid contamination with octanol and placed in a labeled tube.

Stability at Room Temperature

CIO (10 μL 5000 μg / mL) was added to both 0.5 mL of n-octanol and 0.5 mL of water in triplicate. The samples were shaken. At 0 h and 24 h, samples were stored at ca. -20Â ° C. 25 μl of sample was used for analysis.

CIO Extraction Procedure To the octanol sample was added 25 μl of ethanol, 25 μl of water and 300 μl of acetonitrile containing the internal standard 76. To the water sample, 25 μΡ of ethanol, 25 μΡ of octanol and 300 μπΡ of acetonitrile containing the internal standard [60 mL of acetonitrile with 6 μΡ of PNP (1000 μρ / ηΛ)] were added to the water sample. To 25 μΡ of calibration octanol, 25 μΡ of ethanol, 25 μΡ of water and 300 μιΡΡ of acetonitrile containing the internal standard were added. The sample was vortexed for 10 seconds. 200 μΡ of the organic layer was transferred to a washed-off, deactivated autosampler vial. Calculations

1 / weighted linear regression of the concentration was used to quantify the CIO. Complete peak area integration was performed using Analyst version 1.3, Applied Biosystems. For the CIO, the ratios of the peak areas of the analyte to those of the internal PNP standard were used for all quantifications.

The partition coefficient (P) was calculated according to the following detailed equation: P = [Sample Concentration] octanol / [Sample Concentration] Water

Log P = Logio (partition coefficient)

Results:

As shown in Table 9A, the solubility of C10 in both octanol and water is very good in the tested concentration range.

Table 9A. Solubility of CIO in water and octanol 77

Cone. (g / mL) Water Appearance Octanol Appearance 0.800 Clear Clear 4.00 Clear Clear 20.0 Clear Clear 100 Clear Clear Table 9B shows the results of the determination of log P after 1 h and 24 h for CIO. The mean log P after 1 h was 1.97 (n = 3). After 24 h, the concentration in the layers of water and octanol remained the same. The mean log P after 1 h was 1.93 (n = 3).

Table 9B. CIO Log P

Sample Cone. in Water (g / mL). in Octanol Âμg / mL) Log P h-1 1.26 108 1.93 lh-2 1.21 103 1.93 lh-3 1.05 115 2.04 24h-1 1.27 104 1.91 -2 1.17 109 1.97 24h-3 1.28 99.0 0 1.89

The CIO stability study was started at room temperature over 24 h with no continuous stirring. Table 9C shows that the CIO in pure water and octanol is stable for 24 h.

Table 9C. Stability of CIO in water and octanol at room temperature after 24 h 78

Sample Mean (mg / mL) d.p. Percent Remainder 24 h versus 0 g Water-Oh 82.5 3.72 115 Water-24h 95.0 0 21.4 Octanol-Oh 115 3, 06 93 Octanol-24h 107 6.11 EXAMPLE 10

Determination of CIO Penetration in the Human Fingernail

Two protocol-based penetration studies were performed in Hui et al., Journal of Pharmaceutical Sciences, 91 (1): 189-195 (2002) (" Hui protocol "). The objective of this study was to determine and compare the penetration and distribution of CIO in a vehicle in the human nail plate in vitro, relative to 8% m / m cyclopirox in commercial varnish (Penlac®).

MATERIALS AND METHODS

Pharmaceutical Formulation and Product Tested 8% m / m cyclopirox in commercial varnish was manufactured by Dermick (Berwyn, PA). The radiochemical purity and the specific activity of the chemical were determined to be > 95% and 12.5 mCi / mmol, respectively. The study consisted of two groups. The compositions (% by weight) of the pharmaceutical formulations are as follows:

Radiolabeled compound active in four groups.

Groups * Dose (x 14 Product Radioactivity days) Tested (%) (per 10 μΙΟ A (CIO) pq 10 0.19 μΟμ C pq 8 0.22 μϋί (Cyclopirox) * A = CIO group, C = Cyclopiriox group Human Nails

Healthy human finger nail plates were collected from adult human cadavers and stored in a closed vessel at 0-4øC. Prior to the test, the nail plates were carefully washed with normal saline to remove any contamination and then re-hydrated for three hours in a tissue soaked in normal saline. The nail samples were randomly divided into four groups.

Dosing and Surface Washing Procedures

Dose preparation: The radioactivity in each group is approximately 0.19 ± 0.01 and 0.22 ± 0.03 μΟί / 10 μΐϋ, respectively, for the solutions of 14C-C10 (group A) and 14C-cyclopirox (group C) .

Experimental procedure:

Group C Group Day Study Dose washing sample dose sample wash 80 1 DD 2 WDWD 3 WDCWDC 4 w D w D 5 w D w D 6 w DC w DC 7 w D w D 8 w D w D 9 w DC w DC 10 w D w D 11 w D w D 12 w DC w DC 13 w D w D 14 w D w D 15 w C, N w C, NW = once a day before dosing (9 ~ 10 h). D = once daily (9-10 h). C = Sampling / changing the cotton ball after washing prior to topical dosing. N = nail sampling.

Washing Procedure

Surface washing was started in the morning, 10 min before the next dose; the nail surface was washed with cotton swabs as follows: a swab soaked in absolute ethanol, then a swab soaked in absolute ethanol, then a swab soaked in 50% IVORY liquid soap, then a cotton swab dipped in distilled water, then a last swab dipped in distilled water.

The wash samples from each cycle of each nail were pooled and collected by cutting the tip of the swab into scintillation glass vials. 3.0 mL aliquots of methanol were added to each vial to extract the test material. The radioactivity of each sample was measured in a liquid scintillation counter.

Incubation System

A single chamber diffusion cell (permeGear, Inc., Hellerton, PA) was used to store each nail. In close to physiological conditions, a small cotton ball soaked in 0.1 ml of normal saline was placed in the chamber to function as a nail bed and to moisten the nail plate. Every 3 days, 0.1 ml of normal saline was injected into the chamber to keep the cotton ball moist. The nail plate was placed at one end into the receiver (1.0 cm in diameter and 0.5 cm in height). The ventral (inner) surface was placed face down and supported on the wet cotton ball. The cells were placed on a platform in a large glass vessel filled with a saturated sodium phosphate solution to keep the cells at a constant humidity of 40%.

Sampling Instrument The nail sampling instrument has two parts, a platform for the nail sample and a punch. The platform for the nail sample consists of a copper nail holder, three regulators and a nail powder collector. The three regulators allow movement in the vertical direction. The first coarse regulator (at the top) was to change the copper cell and collect dust samples from the manifold. The two other (lower) regulators were for the sampling process. The second coarse regulator allowed 25 mm of movement and the strict regulator provides a movement of 0.20 mm. The nail dust collector was located between the copper cell and the cutting device. The inner shape of the manifold was inverted funnel and the funnel end connected to a vacuum. By placing a circular filter paper inside the funnel, the nail powder samples are collected on the filter paper during the sampling process.

Sample Collection Procedure

After completion of the incubation step, the nail plate of the diffusion cell was transferred to a clean copper nail holder for the sampling procedure. The nail plate was inverted so that the ventral surface (nail bed) is now turned upward and the dorsal (outer) surface, which received the dose, turned downwards. The copper nail holder had an opening at the top of the platform. When the sampling process begins, coarse regulator is set to move the position of the platform until the nail plate only touches the tip of the cutting device. The punch was then turned on and the stiff regulator was turned to push the platform close to the punch, removing a sample from the core of the nail. After the above procedure, they collected sprayed nail samples of about 0.40-0.50 mm deep and 7.9 mm in diameter from the center of the ventral surface (nail bed) of the nail.

Samples of powdered nail were collected in a glass flask and weighed. Aliquots of 5.0 mL of Packard's solution-350 (Packard Instrument Company, Meriden, CT) were added to the scintillation vial to dissolve the powder. The upper portion, intermediate and dorsal layers of the nail center, including the dose application area, were cut to the same sample area diameter and placed in a glass flask containing 5.0 mL of solute -350 Packard. The rest of the nail was also placed in a glass scintillation vial with 5.0 mL of Packard's solution-350.

The amount of nail sample removed was measured by the difference in weight between the nail plate before and after perforation and collection of the core dust.

Radioactivity Measurement

All radioactivity measurements were performed with a Model 1500 Liquid Scintillation Counter (Packard Instrument Company, Downer Grove, IL). The accuracy of the meter was checked using sealed samples of erased or scintillating patterns, as detailed in the instrument manual. The efficiency of the 14C count is equal to or greater than 95%. All fingernail samples pre-treated with Packard's solution-350 at 40øC were incubated for 48 hours, followed by the addition of 10 mL scintillation cocktail (HIONIC-FLUOR, Packard Instrument Company, Meriden, CT). Other samples (standard dose, surface wash and bedding) were mixed directly with Universal ES scintillation cocktail (ICN Biomedicals, Costa Mesa, CA). Radioactivity of background control and test samples was counted for 3 minutes each.

Data Analysis 84

Manually transcribed all sample counts (expressed in dpm) to a computer spreadsheet (Microsoft Excel). The individual and mean (± dp) amounts of the test chemical equivalent in the nail, bedding material and wash samples in dpm, μΟμ, administered dose percentage and mg equivalent, were presented at each time point. The concentration of the tested 14 C-labeled chemicals was calculated from the value based on the specific activity of each product tested with [14 C]. Information on the concentration of the unlabeled tested chemicals in the topical formulation was obtained from manufacturers. The total concentration of the test chemical equivalent is the sum of the concentration of the labeled chemicals tested at 14 ° C and the concentration of the unlabelled tested chemicals. The value of the total amount of test chemical equivalent in each nail sample was calculated on the basis of the radioactivity of the sample and the ratio of the test chemical equivalent in mg total and the radioactivity of the tested chemical. The data were then normalized by dividing by the weight of the sample. The statistical significance of the nail samples from each two groups was analyzed by Studant's t-test.

Terminology

Ventral / Intermediate Center Sample of a powdered nail drawn from the center of the inner surface (facing the nail bed) approximately 0.3 - 0.5 mm deep from the surface. The area is below the nail site that received the dose but does not include the surface that received the dose (the dorsal surface of the nail).

Dorsal / Intermediate Zone The area of the nail site that received the dose. 85

Remaining nail remaining nail that did not receive the dose.

Supporting bed The cotton ball placed inside the diffusion cell of the Teflon chamber to moisten the nail plate and also to receive the chemicals that penetrate through the nail plate.

Surface wash Ethanol (or other organic solvents) and washing soap / water from the surface of the receiving site.

Ring A plastic ring placed at the top of the nail plate to prevent leakage from the site that received the dose to the rest of the nail plate or into the chamber of the cell. Cell wash Ethanol (or other organic solvents) and soap / water inside the diffusion cell.

RESULTS

Characteristics of Nail Samples

For the two groups (Group A and Group C), the thickness of the entire nail plate, the depth of the sample of the ventral surface removed by the cutting instrument, the percentage of the entire thickness of the nail and the weight sample of the powdered nail. There was no statistical difference between the two groups (P > 0.05).

Normalized CIO Weight and Cyclopirox Equivalent on the Tongue FIG. 3 shows, in summary, standard drug equivalents in each portion (layer) of the nail samples. After weight normalization, the concentration of C10 equivalent in the dorsal / intermediate center, ventral / intermediate center and nail residue 86 samples was considerably higher than the equivalent of cyclopirox (p = 0.002).

CIO and Cyclopirox Equivalent in the Cotton Ball Nail Bracket Bed FIG. 4 shows, in summary, CIO and Cyclopirox equivalent in the cotton balls samples of the support bed. As for the normalized weight CIO equivalent in the nail plate samples, the absolute amount of C10 equivalent in each cotton ball sample in group A (after 14 days of dosing) was considerably higher than that of the cyclopirox equivalent in the group C (p = 0.004). The difference between these two products tested was 250 times.

Radioactive Mass Balance of C10- [14C] and Cyclopirox- [C] after 14 days of Treatment Table 5 shows, in summary, the radioactive recovery of the wash, nail samples and cotton ball samples. The cumulative recoveries of carbon-14 radioactivity were 88 ± 9.21 and 89 ± 1.56 percent of the dose applied in group A and group C, respectively. 88% of the radiolabeled material was counted.

CONCLUSION

In this study, the penetration rate of CIO- [14 C] in the topical formulation Anacor and cyclopirox- [14 C] (8% m / m in commercial varnish) was analyzed in the human nail with four different doses and washing methods. 87

The results show that a much larger amount of C10- [14 C] has penetrated the deeper parts of the nail compared to cyclopirox- [14 C]. Tables 3 and 4 show that the amount of C10- [14 C] equivalent in the ventral / intermediate center of the unqueal layer and the cotton ball carrier bed in group A was statistically higher (p = 0.002) than in group C , after a dosing period of 14 days. EXAMPLE 11

Determination of CIO Penetration in Human Nail The aim of the present study was to evaluate and compare periungual COC absorption in a single vehicle using MedPharm's TurChub® model (see http: //www.medpharm.co.uk, specifically http: /www.medpharm.co.uk/downloads/ Skin% 20and% 20and% 20dec% 202003.pdf: seen on February 14, 2006); in a full-scale test. Six replicates were performed involving C10 and Formulations Y (8% m / m cyclopirox in commercial varnish) and Z (Loceryl, 5% m / v amorolfine) were used as reference formulations.

The following materials were used in these tests. These materials were used without any modifications.

A 40 μΐ / οχη2 dose of the test compound C10 in 50:50 propylene glycol: ethyl acetate was applied to the entire thickness of a nail sample, every day, for five days in all. The two reference formulations were applied at the same dose.

TurChub® Zone of Inhibition Assay 88

Placebo CIO test product and reference formulations Y and Z were tested for their ability to inhibit the growth of Trichophyton rubrum (T. rubrum) after penetration through the entire thickness of a human nail using zone of inhibition measurement.

Formulation Efficacy Test

FIGs. 5-9 show the results obtained from the TurChub zone of the inhibition assays. It can be seen that CIO is a potent anti-fungal agent which is able to penetrate through the entire thickness of the nail to produce its effect against the target organism T. rubrum. No zone of inhibition was observed with respect to the Y and Z or placebo formulations of C10. The assay was repeated using the CIO the second time to confirm the result and can be seen in FIGs. 6 and 7, that CIO has zones of inhibition of 100%, 67%, 46%, 57%, 38% and 71% in the first trial, and 74%, 86%, 100%, 82%, 100% and 84% in the second test. Measurements were made from the nail to the first observed growth point. From the results obtained using the MedPharm TurChub zone of the inhibition assay as a test system, it has been found that the CIO test product is a potent antifungal agent and exhibits better results than the commercial reference Y and Z formulations It is apparent from the assays that the compound penetrates through the entire thickness of the nail barrier to manifest antifungal activity. EXAMPLE 12

Determination of CIO Penetration in the Human Fingernail: Dose Response

The optimal dose-response range for penetration into the human nail was found to be between 1% and 15%. Assays for determining the optimal dose-response were performed as follows.

Tests at different concentrations of test compound were performed on nails from the same cadaver. The cadaver's nails were hydrated overnight, cut into 4 squares of the same size and placed in individual poloxamer supports. The test products were formulated in 1%, 2.5%, 5%, 7.5%, 10% and 15% m / v lacquer. A 40 μύ / απ 2 dose was applied to the center of the nail piece and the nails were discarded for 24 hours. The nails were removed from the poloxamer holder. The poloxamer support was analyzed for the amount of compound using LC / MS / MS.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or modifications based thereon will be suggested to the person skilled in the art and are intended to be included within the spirit and scope of this application. All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety for multiple purposes. 90

Claims (24)

A product for use as a medicament and selected from a compound having the structure: F OH and pharmaceutically acceptable salts thereof, optionally wherein the salt is a base addition salt obtained by contacting the neutral form of that compound with a sufficient amount of the desired base in a suitable inert solvent. A product for use as a medicament and selected from a compound having the structure: and pharmaceutically acceptable salts thereof, optionally wherein the salt is a base addition salt obtained by contacting the neutral form of that compound with a sufficient amount of the desired base in a suitable inert solvent. A formulation for pharmaceutical use which comprises: (a) a pharmaceutically acceptable excipient; and (b) a compound having the structure: or pharmaceutically acceptable salts thereof, optionally wherein the salt is a base addition salt obtained by contacting the neutral form of that compound with a sufficient amount of the desired base in a suitable inert solvent. The pharmaceutical formulation according to claim 3, wherein said compound is in a form which is selected from a hydrate, solvate with an alcohol, an adduct with a compound and an adduct with an acid. The pharmaceutical formulation of claim 4, wherein said compound is in the form of a solvate of propylene glycol. The pharmaceutical formulation according to any one of claims 3 to 5, characterized in that it is a topical formulation. The pharmaceutical formulation according to claim 6, characterized in that said compound is present in said pharmaceutical formulation in a concentration of 0.5% to 15% m / v. The pharmaceutical formulation of claim 6, wherein said compound is present in said pharmaceutical formulation in a concentration of 0.1% to 12.5% m / v and optionally, wherein said compound is present in said pharmaceutical formulation in a concentration of about 1% to about 10% and further optionally wherein said compound is present in said pharmaceutical formulation in a concentration of about 1% to about 5% m / v. The pharmaceutical formulation of claim 7 or claim 8, wherein said compound is present in said pharmaceutical formulation in a concentration of about 2% to about 8% m / v. The pharmaceutical formulation of claim 7 or claim 8, wherein said compound is present in said pharmaceutical formulation in a concentration from about 4% to about 9% m / v. The pharmaceutical formulation according to any one of claims 6 to 10, characterized in that the pharmaceutical formulation is selected from a lotion, cream, gel, pencil for lesions, spray, ointment, paste, foam or musse. The pharmaceutical formulation according to any one of claims 6 to 10, characterized in that the formulation is a varnish. The pharmaceutical formulation according to any one of claims 6 to 12, further comprising a gel phase carrier. The pharmaceutical formulation according to any one of claims 6 to 12, further comprising a suitable viscosifying enhancer. 3 The pharmaceutical formulation of any one of claims 6 to 10, wherein the formulation further comprises a simple solution containing an alcohol and optionally including an alcohol and water. The pharmaceutical formulation according to claim 5, characterized in that the alcohol is ethanol. The pharmaceutical formulation according to claim 15, characterized in that the alcohol is propylene glycol. The pharmaceutical formulation according to any one of claims 6 to 10, characterized in that it is a spray which provides said product in an aqueous and / or alcoholic solution. The pharmaceutical formulation of any one of claims 6 to 18, characterized in that it comprises a chelating agent, optionally in which the chelating agent is selected from the group selected from citric acid, ethylenediamine tetraacetic acid (EDTA), ethylene glycol bis (beta-aminoethyl ether) -N, N, Ν ', Ν' -tetraacetic acid (EGTA) and 8-amino-2 - [(2-amino-5-methylphenoxy) methyl] -6-methoxyquinoline N, N ', N'-tetraacetic acid, tetrapotassium salt (QUIN-2). The pharmaceutical formulation of claim 19, wherein said chelating agent is ethylenediamine tetraacetic acid. The pharmaceutical formulation according to claim 17 or claim 18, characterized in that the chelating agent is present in an amount of 0.005% to 2% by weight. The product of claim 1 or claim 2, or the formulation of any one of claims 3 to 21, for use in the treatment or prevention of a cutaneous infection in an animal, optionally, wherein said infection is a cutaneous fungal infection. The product according to claim 1 or claim 2 or the formulation according to any one of claims 3 to 21, characterized in that they are intended for use in inhibiting the growth or death of a fungus on the inside or on the surface of an animal. The product of claim 1 or claim 2, or the formulation of any one of claims 3 to 21, for use in the treatment or prevention of an infection in an animal. The product or formulation according to claim 24, characterized in that said infection is a systemic infection or a nail or periungual infection. The product or formulation according to claim 24, characterized in that said infection is caused by a bacterium; optionally, wherein the bacterium is a gram-positive bacterium; optionally, the gram-positive bacterium is an element selected from Staphylococcus species, Streptococcus species, Bacillus species, Mycobacterium species, Corynebacterium species (Propionibacterium species), Clostridium species, Actinomyces species, Enterococcus species and Streptomyces species; optionally, wherein the bacterium is a gram-negative bacterium; where the gram-negative bacterium is an element selected from Acinetobacter species, Neisseria species, 5 species Pseudomonas, Brucella species, Agrobacterium species, Bordetella species, Escherichia species, Shigelia species, Yersinia species, Salmonella species, Klebsiella species, Enterobacter species , species Haemophilus, species Pasteurella, species Streptobacillus, species esoiroquetal, species Campylobacter, species Vibrio and species Helicobacter. The product or formulation according to claim 24, characterized in that the infection is caused by a fungus or a yeast. The product or formulation according to claim 27, characterized in that said fungus or yeast is a member selected from the species Candida, Trichophyton species, Microsporium species, Aspergillus species, Cryptococcus species, Blastomyces species, Cocciodioides species, species Histoplasma, Paracoccidioides species, Phycomycetes species, Malassezia species, Fusarium species, Epidermophyton species, Scytalidium species, Scopulariopsis species, Alternaria species, Penicillium species, Phialophora species, Rhizopus species, Scedosporium species and Zygomycetes species. The product or formulation according to claim 27, wherein said fungus or yeast is a member selected from Aspergillus fumigatus (A. fumigatus), Blastomyces dermatitidis, Candida Albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, Candida parapsilosis, Candida tropicis, Cocciodiodes immitis, Epidermophyton floccosum, Fusarium solani, Histoplasma capsulatum, Malassezia furfur, Malassezia pachydermatis, Malassezia sympodialis, Microsporum audouinii, Microsporum canis, Microsporum gypseum, Paracoccidioides 6 brasiliensis, Trichophyton mentagrophytes, Trichophyton rubrumr Trichophyton tonsurans. The product or formulation according to claim 27, wherein said fungus or yeast is an element selected from Trichophyton concentricum, Trichophyton violaceum, Trichophyton schoenleinii, Trichophyton verrucosum, Trichophyton soudanense, Microsporum gypseum, Microsporum equinum, Candida guilliermondii , Malassezia globosa, Malassezia obtusa, Malassezia restricta, Malassezia slooffiae and Aspergillus flavus. The product or formulation according to claim 27, characterized in that said fungus or yeast is a dermatophyte. The product or the formulation of claim 24, wherein the infection is a member selected from: chloronychia, paronychia, erysipeloid, onicorrex, gonorrhea, swimming pool granuloma, larva migrans, leprosy, Orf nodule, nodules of spermatocytosis, syphilis, cutaneous verrucous tuberculosis, tularemia, mycotic keratitis, surface oculomycosis, endogenous oculomycosis, lobomycosis, mycetoma, piedra, tinea versicolor, had the body, had crural, had feet, had beard, had head, had nigra, otocomicose, had favosa, chromomycosis and had imbricata. The product or formulation according to claim 24 or claim 25, wherein said infection is onychomycosis. The product or formulation according to claim 24, wherein the infection is unguium . The product or formulation according to claim 34, wherein the nail has been caused by a dermatophyte selected from Trichophyton rubrum and Trichophyton menthagrophytes. The product or formulation according to claim 24 or claim 25, wherein said animal is a human, bovine, goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey. The product or formulation according to claim 36, characterized in that the animal is a human. The product according to any one of claims 1 and 2 or 22 to 27 or the pharmaceutical formulations according to any one of claims 4 to 38, characterized in that they are intended for use by topical application. The product or formulation according to any one of claims 24 to 27, characterized in that the compound or formulation is for administration to the site which is selected from skin, nail, hair, hull and jaw. area of the A composition for topical application, e.g. in cosmetics, and characterized in that it contains a compound: The α or OH Or a pharmaceutically acceptable salt thereof, optionally wherein the salt is a base addition salt obtained by contacting the neutral form of that compound with a sufficient amount of the desired base in a suitable inert solvent, the composition being selected from (i) lotions, creams , gels, pencils for lesions, sprays, ointments, pastes, foams and mousses; and (ii) compositions having a component selected from inert fillers, anti-irritants, tackifiers, excipients, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactants, emollients, preservatives, buffering agents, other permeation enhancers. A topical gel formulation comprising (a) a compound of formula OH or a pharmaceutically acceptable salt thereof, optionally wherein the salt is a base addition salt obtained by contacting the neutral form of that compound with a sufficient amount of the desired base in a suitable inert solvent, and (b) a gel phase carrier. 9 The formulation of any one of claims 3 to 39 or 41, further comprising an additional pharmaceutically effective agent, e.g. an anti-inflammatory agent and / or an acne treatment agent. The subject matter of any one of the preceding claims wherein the compound is in the form of the acid. 10